Updated on 2025/09/06

写真a

 
OHARA Naoya
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
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Degree

  • 博士（歯学） ( 1995.12   長崎大学 )

Research Interests

  • pathogenic bacteria

  • 病原細菌

Research Areas

  • Life Science / Oral biological science

  • Life Science / Bacteriology

Research History

  • 岡山大学学術研究院医歯薬学域口腔微生物学分野 教授

    2021.4

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  • 岡山大学大学院医歯薬学総合研究科口腔微生物学分野 教授

    2009.7 - 2021.3

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  • 長崎大学大学院医歯薬学総合研究科口腔微生物学分野 助教授

    2003.4 - 2007.1

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Committee Memberships

  • Scientific Reports   Editorial Board  

    2045.6   

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    Committee type：Other

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  • 日本細菌学会   理事  

    2024.1   

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    Committee type：Academic society

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  • 歯科基礎医学会   常任理事  

    2020.4   

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    Committee type：Academic society

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  • Journal of Oral Biosciences   編集委員  

    2018.1   

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    Committee type：Academic society

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  • 歯科基礎医学会   理事  

    2016.5 - 2020.3   

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    Committee type：Academic society

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  • 歯科基礎医学会   代議員（評議員）  

    2012.2   

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    Committee type：Academic society

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  • 日本細菌学会   評議員  

    1997.1   

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    Committee type：Academic society

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Papers

  • Mycobacterium tuberculosis bacillus induces pyroptosis in human lung fibroblasts Reviewed

    Takemasa Takii, Hiroyuki Yamada, Chihiro Motozono, Sho Yamasaki, Jordi B. Torrelles, Joanne Turner, Aoi Kimishima, Yukihiro Asami, Naoya Ohara, Shigeaki Hida, Hidetoshi Hayashi, Kikuo Onozaki

    mSphere   10 ( 6 )   2025.6

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

    ABSTRACT

    We previously reported that live, but not dead, virulent Mycobacterium tuberculosis ( Mtb ) H37Rv bacilli induce cell death in human lung fibroblast cell lines, MRC-5, MRC-9, and TIG-1. Here, using two distinct Mtb strains from two different lineages (HN878 lineage 2 and H37Rv lineage 4), we confirmed cell death at day 2 after infection with a device that measures cell growth/cytotoxicity in real time (Maestro-Z [AXION]). Mtb bacilli uptake by the fibroblast was confirmed with a transmission electron microscope on day 2. Expressions of inflammatory cytokines and interleukin (IL)−1β, IL-6, and IL-8 were observed when exposed to live, but not dead bacteria. The cell death of fibroblasts induced by both Mtb strains tested was prevented by caspase-1/4 and NLRP3 inflammasome inhibitors, but not by caspase-3 and caspase-9 inhibitors. Therefore, we classified the fibroblast cell death by Mtb infection as pyroptosis. To investigate the biological and pathological relevance of fibroblast cell death by Mtb infection, we performed dual RNA-Seq analysis on Mtb within fibroblasts and Mtb -infected fibroblasts at day 2. In Mtb bacilli tcrR , secE2 , ahpD , and mazF8 genes were highly induced during infection. These genes play roles in survival in a hypoxic environment, production of a calcium-binding protein-inducing cytokine, and regulation of transcription in a toxin-antitoxin system. The gene expressions of IL-1β, IL-6, and IL-8, caspase-4, and NLRP3, but not of caspase-3 and caspase-9, were augmented in Mtb bacilli-infected fibroblasts. Taken together, our study suggests that Mtb bacilli attempt to survive in lung fibroblasts and that pyroptosis of the host fibroblasts activates the immune system against the infection.

    IMPORTANCE

    The role of “non-classical immune cells,” that is, fibroblasts, epithelial cells, adipocytes, etc., except for the “classical immune cells,” that is, macrophages and lymphoid cells, is not well known in the infection of Mtb bacilli. We have previously found that live, but not dead, Mtb bacilli induce cell death in human lung fibroblasts, except in human macrophages and monocytes. The present study reveals that fibroblasts ingest Mtb bacilli the same as macrophages and that in vivo Mtb bacilli within fibroblasts attempt to survive in the host cells, and pyroptosis, including the production of inflammatory cytokines, is induced in the Mtb-infected fibroblasts. Our results suggest that pyroptosis of the host fibroblasts activates the immune system against the infection.

    DOI： 10.1128/msphere.00110-25

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  • BMP-2 generates a functional bone marrow niche by inducing the differentiation of local mesenchymal cells into CAR cells Reviewed

    Mitsuaki Ono, Ikue Tosa, Anh Tuan Dang, Ziyi Wang, Maiko Kimura, Wakana Kitagawa, Kei Ishibashi, Hang Thuy Do, Kun Zhao, Emilio Satoshi Hara, Noboru Asada, Takashi Nagasawa, Toshitaka Oohashi, Naoya Ohara, Takuo Kuboki

    Blood Advances   2025.3

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

    Ectopic bone marrow (eBM) holds tremendous potential as an artificial organ, serving not only in stem cell transplantation therapies but also as a controlled experimental system for analyzing cellular dynamics and interactions between cells and the matrix during the formation, maintenance, and aging of bone marrow (BM). Although bone morphogenetic protein (BMP)-2 has been reported to induce eBM formation, it remains unproven whether BMP-2 induced eBM (BMP-eBM) can provide a functional BM niche that is comparable to native BM in long bones (LB-BM). In this study, through the use of single-cell RNA sequencing and transplantation models, we demonstrate for the first time that BMP-eBM displays a microstructure, cellular composition, and functional hematopoiesis similar to LB-BM. BMP-eBM establishes an optimized microenvironment capable of supporting hematopoietic stem cells (HSCs) and CXC-chemokine-ligand-12 (CXCL12)-abundant reticular (CAR) cells, which are critical components of the BM niche. Significantly, BMP-eBM was able to restore survival in irradiated mice. Through parabiosis and cell transplantation experiments, we identified that in situ adipose tissue-derived CD51highCxcl12-GFP- cells are the principal source of CAR cells within BMP-eBM. Furthermore, BMP-eBM can be isolated and, after preconditioning, re-transplanted as an independent, functional hematopoietic organ. In conclusion, our study confirms that BMP-eBM functions effectively as a hematopoietic organ, capable of supporting and maintaining a functional BM niche. These findings underscore BMP-2 as a crucial molecule for eBM generation and suggest its potential for addressing BM-related diseases and for use as a platform for in vitro and ex vivo biomedical applications.

    DOI： 10.1182/bloodadvances.2024014062

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  • Mycobacterial DNA-binding protein 1 is critical for BCG survival in stressful environments and simultaneously regulates gene expression. Reviewed International journal

    Amina K Shaban, Gebremichal Gebretsadik, Mariko Hakamata, Hayato Takihara, Erina Inouchi, Akihito Nishiyama, Yuriko Ozeki, Yoshitaka Tateishi, Yukiko Nishiuchi, Takehiro Yamaguchi, Naoya Ohara, Shujiro Okuda, Sohkichi Matsumoto

    Scientific reports   13 ( 1 )   14157 - 14157   2023.8

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    Language：English   Publishing type：Research paper (scientific journal)  

    Survival of the live attenuated Bacillus Calmette-Guérin (BCG) vaccine amidst harsh host environments is key for BCG effectiveness as it allows continuous immune response induction and protection against tuberculosis. Mycobacterial DNA binding protein 1 (MDP1), a nucleoid associated protein, is essential in BCG. However, there is limited knowledge on the extent of MDP1 gene regulation and how this influences BCG survival. Here, we demonstrate that MDP1 conditional knockdown (cKD) BCG grows slower than vector control in vitro, and dies faster upon exposure to antibiotics (bedaquiline) and oxidative stress (H2O2 and menadione). MDP1-cKD BCG also exhibited low infectivity and survival in THP-1 macrophages and mice indicating possible susceptibility to host mediated stress. Consequently, low in vivo survival resulted in reduced cytokine (IFN-gamma and TNF-alpha) production by splenocytes. Temporal transcriptome profiling showed more upregulated (81-240) than downregulated (5-175) genes in response to MDP1 suppression. Pathway analysis showed suppression of biosynthetic pathways that coincide with low in vitro growth. Notable was the deferential expression of genes involved in stress response (sigI), maintenance of DNA integrity (mutT1), REDOX balance (WhiB3), and host interactions (PE/PE_PGRS). Thus, this study shows MDP1's importance in BCG survival and highlights MDP1-dependent gene regulation suggesting its role in growth and stress adaptation.

    DOI： 10.1038/s41598-023-40941-9

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  • Synthetic engineering and biological containment of bacteriophages Reviewed

    Shoichi Mitsunaka, Kohei Yamazaki, Ajeng K. Pramono, Megumi Ikeuchi, Tomoe Kitao, Naoya Ohara, Tomoko Kubori, Hiroki Nagai, Hiroki Ando

    Proceedings of the National Academy of Sciences   119 ( 48 )   e2206739119   2022.11

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Proceedings of the National Academy of Sciences  

    The serious threats posed by drug-resistant bacterial infections and recent developments in synthetic biology have fueled a growing interest in genetically engineered phages with therapeutic potential. To date, many investigations on engineered phages have been limited to proof of concept or fundamental studies using phages with relatively small genomes or commercially available “phage display kits”. Moreover, safeguards supporting efficient translation for practical use have not been implemented. Here, we developed a cell-free phage engineering and rebooting platform. We successfully assembled natural, designer, and chemically synthesized genomes and rebooted functional phages infecting gram-negative bacteria and acid-fast mycobacteria. Furthermore, we demonstrated the creation of biologically contained phages for the treatment of bacterial infections. These synthetic biocontained phages exhibited similar properties to those of a parent phage against lethal sepsis in vivo. This efficient, flexible, and rational approach will serve to accelerate phage biology studies and can be used for many practical applications, including phage therapy.

    DOI： 10.1073/pnas.2206739119

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  • Porphyromonas gingivalis gingipains induce cyclooxygenase-2 expression and prostaglandin E2 production via ERK1/2-activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 cascades Reviewed International journal

    Masaaki Nakayama, Mariko Naito, Kazuhiro Omori, Shintaro Ono, Koji Nakayama, Naoya Ohara

    Journal of Immunology   208 ( 5 )   1146 - 1154   2022.5

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Porphyromonas gingivalis is commonly known as one of the major pathogens contributing to periodontitis, and its persistent infection may increase the risk for the disease. The proinflammatory mediators, including IL-6, TNF-α, and cyclooxygenase-2 (COX-2)/PGE2, are closely associated with progression of periodontitis. In this study, we focused on the cysteine protease "gingipains," lysine-specific gingipain, arginine-specific gingipain (Rgp) A, and RgpB, produced by P. gingivalis, and used the wild-type strain and several gene-deletion mutants (rgpA, rgpB, kgp, and fimA) to elucidate the involvement of gingipains in COX-2 expression and PGE2 production. We infected human monocytes, which are THP-1 cells and primary monocytes, with these bacterial strains and found that gingipains were involved in induction of COX-2 expression and PGE2 production. We have shown that the protease activity of gingipains was crucial for these events by using gingipain inhibitors. Furthermore, activation of ERK1/2 and IκB kinase was required for gingipain-induced COX-2 expression/PGE2 production, and these kinases activated two transcription factors, c-Jun/c-Fos (AP-1) and NF-κB p65, respectively. In particular, these data suggest that gingipain-induced c-Fos expression via ERK is essential for AP-1 formation with c-Jun, and activation of AP-1 and NF-κB p65 plays a central role in COX-2 expression/PGE2 production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE2 production via activation of MEK/ERK/AP-1 and IκB kinase/NF-κB p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.

    DOI： 10.4049/jimmunol.2100866

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  • Attempt of thyX gene silencing and construction of a thyX deleted clone in a Mycobacterium bovis BCG Reviewed

    Yuki Arimura, Yusuke Minato, Takayuki Wada, Masaaki Nakayama, Ayako Ryumon, Nao Hirata, Chie Nakajima, Yasuhiko Suzuki, Manabu Ato, Kazuo Kobayashi, Naoko Ohara, Seiji Iida, Naoya Ohara

    Microbiology and Immunology   66 ( 1 )   10 - 14   2022.1

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1111/1348-0421.12944

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/1348-0421.12944

  • GRIM‐19 is a target of mycobacterial Zn 2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation Reviewed

    Tomomi Kurane, Tetsuro Matsunaga, Tomoaki Ida, Kazuko Sawada, Akira Nishimura, Masayuki Fukui, Masayuki Umemura, Masaaki Nakayama, Naoya Ohara, Sohkichi Matsumoto, Takaaki Akaike, Goro Matsuzaki, Giichi Takaesu

    The FASEB Journal   36 ( 1 )   e22096   2022.1

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1096/fj.202101074rr

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.202101074RR

  • Comparative Study of the Susceptibility to Oxidative Stress between Two Types of Mycobacterium bovis BCG Tokyo 172. Reviewed International journal

    Keiichi Taniguchi, Daisuke Hayashi, Naomi Yasuda, Mao Nakayama, Kaori Yazawa, Shouta Ogawa, Yuji Miyatake, Saki Suda, Haruka Tomita, Miki Tokuda, Saotomo Itoh, Jun-Ichi Maeyama, Naoya Ohara, Saburo Yamamoto, Shigeaki Hida, Kikuo Onozaki, Takemasa Takii

    mSphere   6 ( 2 )   e00111-21   2021.3

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    Language：English   Publishing type：Research paper (scientific journal)  

    Genomic analysis revealed that the vaccine seed lot of Mycobacterium bovis bacillus Calmette-Guérin (BCG) Tokyo 172 contains two subclones (types I and II), but their phenotypic differences have not been elucidated. In this study, we compared the susceptibility of bacilli types I and II to oxidative stress in vitro and within host cells. Notably, the subclones displayed similar superoxide dismutase activity; however, foam height in the catalase test and lysate catalase/peroxidase activity were higher for type I bacilli than for type II bacilli. Additionally, type I bacilli were less susceptible to hydrogen peroxide (H2O2) than type II bacilli. After exposure to H2O2, antioxidative stress response genes katG, ahpC, sodA, and trxA were more strongly induced in type I bacilli than in type II bacilli. Further, we investigated cell survival in macrophages. Fewer type II bacilli were recovered than type I bacilli. However, in the presence of apocynin, a specific inhibitor of NADPH oxidase, type II recovery was greater than that of type I. The production of interleukin 1β (IL-1β), IL-12 p40, and tumor necrosis factor alpha (TNF-α) was higher in type I bacillus-infected macrophages than in type II bacillus-infected macrophages. The proportions of type I and type II bacilli in vaccine lots over 3 years (100 lots) were 97.6% ± 1.5% and 2.4% ± 1.5%, respectively. The study results illustrated that type I bacilli are more resistant to oxidative stress than type II bacilli. Overall, these findings provide important information in terms of the quality control and safety of BCG Tokyo 172 vaccine.IMPORTANCE This study revealed the difference of in vivo and in vitro antioxidative stress properties of BCG Tokyo 172 types I and II as one of the bacteriological characteristics. In particular, the bacilli exhibited differences in catalase/peroxidase activity, which could explain their different protective effects against infection. The differences correlated with survival in the host cell and the production of proinflammatory cytokines to protect against infection by Mycobacterium tuberculosis The proportion of bacilli types I and II in all commercial lots of BCG Tokyo 172 over 3 years (100 lots) was constant. The findings also highlighted the importance of analyzing their content for quality control during vaccine production.

    DOI： 10.1128/mSphere.00111-21

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  • Point mutation in the stop codon of MAV_RS14660 increases the growth rate of Mycobacterium avium subspecies hominissuis Reviewed

    Tomomi Kawakita, Tetsu Mukai, Mitsunori Yoshida, Hiroyuki Yamada, Masaaki Nakayama, Yuji Miyamoto, Masato Suzuki, Noboru Nakata, Takemasa Takii, Akihide Ryo, Naoya Ohara, Manabu Ato

    Microbiology   167 ( 2 )   001007   2021.2

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Microbiology Society  

    <italic>
    <named-content content-type="subspecies">
    <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://doi.org/10.1601/nm.14878" xlink:type="simple">Mycobacterium avium</ext-link>
    </named-content>
    </italic> subspecies <italic>
    <named-content content-type="subspecies">
    <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://doi.org/10.1601/nm.14878" xlink:type="simple">hominissuis</ext-link>
    </named-content>
    </italic> (MAH) is a pathogen that causes various non-tuberculous mycobacterial diseases in humans and animals worldwide. Among the genus, MAH is characterized by relatively slow growth. Here, we isolated a rapidly growing variant of the MAH 104 strain. The variant strain (named N104) exhibited an enhanced growth rate and higher motility compared to the parent MAH 104 strain (P104). Whole-genome sequencing analysis of N104 revealed the loss of the stop codon of <italic>MAV_RS14660</italic> due to a single nucleotide replacement, resulting in the substitution of the codon for tryptophan. Notably, exclusion of the stop codon ligated the open reading frames and caused the fusion of two adjacent proteins. A revertant parent strain, in which a mutation was introduced to restore the stop codon, revealed that elimination of the stop codon in <italic>MAV_RS14660</italic> was responsible for the N104 phenotype. Furthermore, we analysed the phenotypes of the parent and mutated strains by determining the functions of the <italic>MAV_RS14660</italic> and <italic>MAV_RS14655</italic> coding regions flanking the stop codon. The mutant strains, expected to express a fusion protein, exhibited increased resistance to antimicrobial drugs and exogenous copper toxicity compared to that of the parent strains. These findings suggest that the fusion of the <italic>MAV_RS14660</italic>- and <italic>MAV_RS14655</italic>-encoding regions in the mutant N104 strain could be related to the modified functions of these intrinsic proteins.

    DOI： 10.1099/mic.0.001007

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  • Roles of Porphyromonas gulae proteases in bacterial and host cell biology. Reviewed International journal

    Alam Saki Urmi, Hiroaki Inaba, Ryota Nomura, Sho Yoshida, Naoya Ohara, Fumitoshi Asai, Kazuhiko Nakano, Michiyo Matsumoto-Nakano

    Cellular microbiology   23 ( 8 )   e13312   2021.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    Porphyromonas gulae, an animal-derived periodontal pathogen, expresses several virulence factors, including fimbria, lipopolysaccharide (LPS), and proteases. We previously reported that its invasive efficiency was dependent on fimbriae types. In addition, P. gulae LPS increased inflammatory responses via toll-like receptors. The present study was conducted to investigate the involvement of P. gulae proteases in bacterial and host cell biology. P. gulae strains showed an ability to agglutinate mouse erythrocytes and also demonstrated coaggregation with Actinomyces viscosus, while the protease inhibitors antipain, PMSF, TLCK, and leupeptin diminished P. gulae proteolytic activity, resulting in inhibition of hemagglutination and coaggregation with A. viscosus. In addition, specific proteinase inhibitors were found to reduce bacterial cell growth. P. gulae inhibited Ca9-22 cell proliferation in a multiplicity of infection- and time-dependent manner. Additionally, P. gulae-induced decreases in cell contact and adhesion-related proteins were accompanied by a marked change in cell morphology from well spread to rounded. In contrast, inhibition of protease activity prevented degradation of proteins, such as E-cadherin, β-catenin, and focal adhesion kinase, and also blocked inhibition of cell proliferation. Together, these results indicate suppression of the amount of human proteins, such as γ-globulin, fibrinogen and fibronectin, by P. gulae proteases, suggesting that a novel protease complex contributes to bacterial virulence. This article is protected by copyright. All rights reserved.

    DOI： 10.1111/cmi.13312

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  • Construction and characterization of the PGN_0296 mutant of Porphyromonas gingivalis Reviewed

    Abu Saleh Muhammad Shahriar, Shintaro Ono, Masaaki Nakayama, Naoko Ohara, Naoya Ohara

    Journal of Oral Biosciences   62 ( 4 )   322 - 326   2020.12

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.job.2020.09.007

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  • Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice. Reviewed International journal

    Ryo Ozuru, Shohei Wakao, Takahiro Tsuji, Naoya Ohara, Takashi Matsuba, Muhammad Y Amuran, Junko Isobe, Morio Iino, Naoki Nishida, Sari Matsumoto, Kimiharu Iwadate, Noriko Konishi, Kaori Yasuda, Kosuke Tashiro, Misato Hida, Arisato Yadoiwa, Shinsuke Kato, Eijiro Yamashita, Sohkichi Matsumoto, Yoichi Kurozawa, Mari Dezawa, Jun Fujii

    Molecular therapy   28 ( 1 )   100 - 118   2020.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 × 109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 × 104 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection.

    DOI： 10.1016/j.ymthe.2019.09.023

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  • Construction and characterization of a PGN_0297 mutant of Porphyromonas gingivalis: evidence of the contribution of PGN_0297 to gingipain activity. Reviewed

    Ono S, Nakayama M, Tachibana M, Shahriar ASM, Heling W, Takashiba S, Ohara N

    Acta Medica Okayama   73 ( 4 )   315 - 323   2019.8

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    The periodontal pathogen Porphyromonas gingivalis shows colonial pigmentation on blood agar and produces gingipains (Kgp, RgpA, and RgpB), cysteine proteases involved in an organism's virulence and pigmentation. We showed previously that deletion of the PGN_0300 gene abolished the pigmentation activity and reduced the proteolytic activity of gingipains. The role of the PGN_0297 gene, which consists of an operon with the PGN_0300 gene, is unclear. Herein we examined the effect of PGN_0297 gene deletion on the pigmentation and proteolytic activities and transcriptional levels of gingipains. A PGN_0297 gene deletion mutant (ΔPGN_0297) did not exhibit the pigmentation. The proteolytic activity of the gingipains was decreased in the culture supernatant and on the cell surface of ΔPGN_0297. The mutant ΔPGN_0297 failed to attenuate Akt phosphorylation at Thr308 and Ser473, but both phosphorylations were attenuated in the wild-type and its complementation strain. The deletion of PGN_0297 gene did not substantially affect the transcriptional levels of the gingipain genes kgp, rgpA, and rgpB. Taken together, these results indicate that PGN_0297 is closely involved in the secretion and maturation of gingipains.

    DOI： 10.18926/AMO/56933

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  • Sequential Sensing by TLR2 and Mincle Directs Immature Myeloid Cells to Protect against Invasive Group A Streptococcal Infection in Mice Reviewed

    Takayuki Matsumura, Tadayoshi Ikebe, Koji Arikawa, Masahito Hosokawa, Michio Aiko, Aoi Iguchi, Ikuko Togashi, Sayaka Kai, Sakiko Ohara, Naoya Ohara, Makoto Ohnishi, Haruo Watanabe, Kazuo Kobayashi, Haruko Takeyama, Sho Yamasaki, Yoshimasa Takahashi, Manabu Ato

    Cell Reports   27 ( 2 )   561 - 571.e6   2019.4

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.celrep.2019.03.056

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  • Discrimination of Mycobacterium leprae and Mycobacterium haemophilum in Clinical Isolates and Specimens by Multiplex PCR Assay and Prediction of Drug Susceptibility. Reviewed International journal

    Naoya Kitaoka, Hanako Fukano, Mitsunori Yoshida, Yuji Miyamoto, Shuichi Mori, Norihisa Ishii, Manabu Ato, Naoya Ohara, Yoshihiko Hoshino

    Journal of clinical microbiology   57 ( 2 )   e01760-18   2019.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1128/JCM.01760-18

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  • Mycobacterial infection induces eosinophilia and production of α-defensin by eosinophils in mice. Reviewed

    Khatun A, Sakurai M, Sakai Y, Tachibana M, Ohara N, Morimoto M

    The Journal of veterinary medical science   81 ( 1 )   138 - 142   2019.1

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    It has been well known in humans that eosinophil infiltration into the site of inflammation and eosinophilia occur in mycobacterial infections. However, the role of eosinophils against the mycobacterium is unclear. We showed in previous study that in situ mouse eosinophils infiltrated into tissues produce α-defensin, an anti-bacterial peptide. We investigated in this study whether eosinophils reacting to mycobacteria produce α-defensin in mice and whether it can be used as a model. We showed that mycobacterial infection induced blood eosinophilia and infiltration of α-defensin producing eosinophils that to surround mycobacteria at the site of infection. These findings were usually seen during human mycobacterial infection. We established a good model to study host defense mechanism against mycobacteria through α-defensin via eosinophils.

    DOI： 10.1292/jvms.18-0619

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  • C-terminal intrinsically disordered region-dependent organization of the mycobacterial genome by a histone-like protein Reviewed

    Anna Savitskaya, Akihito Nishiyama, Takehiro Yamaguchi, Yoshitaka Tateishi, Yuriko Ozeki, Masaaki Nameta, Tomohiro Kon, Shaban A. Kaboso, Naoya Ohara, Olga V. Peryanova, Sohkichi Matsumoto

    Scientific Reports   8 ( 1 )   2018.12

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/s41598-018-26463-9

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  • Interleukin-21 Induces Short-Lived Effector CD8(+) T Cells but Does Not Inhibit Their Exhaustion after Mycobacterium bovis BCG Infection in Mice Reviewed

    Noguchi Naoto, Nakamura Risa, Hatano Shinya, Yamada Hisakata, Sun Xun, Ohara Naoya, Yoshikai Yasunobu

    INFECTION AND IMMUNITY   86 ( 8 )   2018.8

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    DOI： 10.1128/IAI.00147-18

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  • Recovery of mycobacteriophages from archival stocks stored for approximately 50 years in Japan Reviewed

    Takako Ujihara, Jumpei Uchiyama, Tadahiro Nasukawa, Hiroki Ando, Hironobu Murakami, Naoya Ohara, Midori Ogawa, Toshio Yamazaki, Masanori Daibata, Masahiro Sakaguchi, Shigenobu Matsuzaki

    Archives of Virology   163 ( 7 )   1915 - 1919   2018.7

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  • Genome sequences of 12 mycobacteriophages recovered from archival stocks in Japan Reviewed

    Jumpei Uchiyama, Keijiro Mizukami, Koji Yahara, Shin Ichiro Kato, Hironobu Murakami, Tadahiro Nasukawa, Naoya Ohara, Midori Ogawa, Toshio Yamazaki, Shigenobu Matsuzaki, Masahiro Sakaguchi

    Genome Announcements   6 ( 25 )   2018.6

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  • The influence of zoledronate and teriparatide on gamma delta T cells in mice Reviewed

    Eiki Yamachika, Yuichi Matsui, Masakazu Matsubara, Tatsushi Matsumura, Naoki Nakata, Norifumi Moritani, Atsushi Ikeda, Hidetsugu Tsujigiwa, Naoya Ohara, Seiji Iida

    Journal of Dental Sciences   12 ( 4 )   333 - 339   2017.12

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    DOI： 10.1016/j.jds.2017.03.007

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  • Molecular mechanisms of Porphyromonas gingivalis-host cell interaction on periodontal diseases Invited Reviewed

    Masaaki Nakayama, Naoya Ohara

    Japanese Dental Science Review   53 ( 4 )   134 - 140   2017.11

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  • Novel function of Porphyromonas gingivalis gingipains in the PI3K/Akt signaling pathway Invited Reviewed

    Nakayama Masaaki, Ohara Naoya

    JOURNAL OF ORAL BIOSCIENCES   59 ( 3 )   131 - 134   2017.8

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  • IL-21 inhibits IL-17A-producing T-cell response after infection with Bacillus Calmette-Guerin via induction of apoptosis Reviewed

    Yinxia Huang, Yumiko Matsumura, Shinya Hatano, Naoto Noguchi, Tesshin Murakami, Yoichiro Iwakura, Xun Sun, Naoya Ohara, Yasunobu Yoshikai

    INNATE IMMUNITY   22 ( 8 )   588 - 597   2016.11

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  • Antitumor activity of recombinant Bacille Calmette-Guerin secreting interleukin-15-Ag85B fusion protein against bladder cancer Reviewed

    Ario Takeuchi, Masatoshi Eto, Katsunori Tatsugami, Masaki Shiota, Hisakata Yamada, Yoriyuki Kamiryo, Takashi Dejima, Eiji Kashiwagi, Keijiro Kiyoshima, Junichi Inokuchi, Ryosuke Takahashi, Akira Yokomizo, Naoya Ohara, Yasunobu Yoshikai

    INTERNATIONAL IMMUNOPHARMACOLOGY   35   327 - 331   2016.6

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    DOI： 10.1016/j.intimp.2016.03.007

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  • Recombinant Mycobacterium bovis bacillus Calmette-Guerin expressing Ag85B-IL-7 fusion protein enhances IL-17A-producing innate gamma delta T cells Reviewed

    Shinya Hatano, Toshiki Tamura, Masayuki Umemura, Goro Matsuzaki, Naoya Ohara, Yasunobu Yoshikai

    VACCINE   34 ( 22 )   2490 - 2495   2016.5

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    DOI： 10.1016/j.vaccine.2016.03.096

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  • Involvement of an Skp-Like Protein, PGN_0300, in the Type IX Secretion System of Porphyromonas gingivalis Reviewed

    Yuko Taguchi, Keiko Sato, Hideharu Yukitake, Tetsuyoshi Inoue, Masaaki Nakayama, Mariko Naito, Yoshio Kondo, Konami Kano, Tomonori Hoshino, Koji Nakayama, Shogo Takashiba, Naoya Ohara

    INFECTION AND IMMUNITY   84 ( 1 )   230 - 240   2016.1

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    DOI： 10.1128/IAI.01308-15

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  • Deep sequencing analysis of the heterogeneity of seed and commercial lots of the bacillus Calmette-Guerin (BCG) tuberculosis vaccine substrain Tokyo-172 Reviewed

    Takayuki Wada, Fumito Maruyama, Tomotada Iwamoto, Shinji Maeda, Taro Yamamoto, Ichiro Nakagawa, Saburo Yamamoto, Naoya Ohara

    SCIENTIFIC REPORTS   5   17827   2015.12

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    DOI： 10.1038/srep17827

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  • Glycopeptidolipid of Mycobacterium smegmatis J15cs Affects Morphology and Survival in Host Cells Reviewed

    Nagatoshi Fujiwara, Naoya Ohara, Midori Ogawa, Shinji Maeda, Takashi Naka, Hatsumi Taniguchi, Saburo Yamamoto, Minoru Ayata

    PLOS ONE   10 ( 5 )   e0126813   2015.5

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  • Attenuation of the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway by Porphyromonas gingivalis Gingipains RgpA, RgpB, and Kgp Reviewed

    Masaaki Nakayama, Tetsuyoshi Inoue, Mariko Naito, Koji Nakayama, Naoya Ohara

    JOURNAL OF BIOLOGICAL CHEMISTRY   290 ( 8 )   5190 - 5202   2015.2

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    DOI： 10.1074/jbc.M114.591610

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  • Role of extracytoplasmic function sigma factors in biofilm formation of Porphyromonas gingivalis Reviewed

    Satosu Onozawa, Yuichiro Kikuchi, Kazuko Shibayama, Eitoyo Kokubu, Masaaki Nakayama, Tetsuyoshi Inoue, Keisuke Nakano, Yukinaga Shibata, Naoya Ohara, Koji Nakayama, Kazuyuki Ishihara, Toshiyuki Kawakami, Hiromasa Hasegawa

    BMC Oral Health   15   4   2015.1

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    DOI： 10.1186/1472-6831-15-4

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  • Characterization of the tripartite drug efflux pumps of Porphyromonas gingivalis ATCC 33277 Reviewed

    Tetsuyoshi Inoue, Masaaki Nakayama, Yuko Taguchi, Konami Kano, Miyuu Ono, Yurika Shimizu, Teruo Kuroda, Naoya Ohara

    NEW MICROBIOLOGICA   38 ( 1 )   101 - 107   2015.1

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  • Development of a novel plasmid vector pTIO-1 adapted for electrotransformation of Porphyromonas gingivalis Reviewed

    Junpei Tagawa, Tetsuyoshi Inoue, Mariko Naito, Keiko Sato, Tomomi Kuwahara, Masaaki Nakayama, Koji Nakayama, Takashi Yamashiro, Naoya Ohara

    JOURNAL OF MICROBIOLOGICAL METHODS   105   174 - 179   2014.10

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    DOI： 10.1016/j.mimet.2014.07.032

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  • Hemoglobin Receptor Protein from Porphyromonas gingivalis Induces Interleukin-8 Production in Human Gingival Epithelial Cells through Stimulation of the Mitogen-Activated Protein Kinase and NF-kappa B Signal Transduction Pathways Reviewed

    Yuki Fujita, Masaaki Nakayama, Mariko Naito, Eiki Yamachika, Tetsuyoshi Inoue, Koji Nakayama, Seiji Iida, Naoya Ohara

    INFECTION AND IMMUNITY   82 ( 1 )   202 - 211   2014.1

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    DOI： 10.1128/IAI.01140-12

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  • Evaluating efficacy of bacteriophage therapy against Staphylococcus aureus infections using a silkworm larval infection model Reviewed

    Iyo Takemura-Uchiyama, Jumpei Uchiyama, Shin ichiro Kato, Tetsuyoshi Inoue, Takako Ujihara, Naoya Ohara, Masanori Daibata, Shigenobu Matsuzaki

    FEMS Microbiology Letters   347 ( 1 )   52 - 60   2013.10

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  • Antigen 85A and mycobacterial DNA-binding protein 1 are targets of immunoglobulin G in individuals with past tuberculosis. Reviewed

    Osada-Oka Mayuko, Tateishi Yoshitaka, Hirayama Yukio, Ozeki Yuriko, Niki Mamiko, Kitada Seigo, Maekura Ryoji, Tsujimura Kunio, Koide Yukio, Ohara Naoya, Yamamoto Taro, Kobayashi Kazuo, Matsumoto Sohkichi

    Microbiol Immunol   57 ( 1 )   30 - 37   2013.1

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    DOI： 10.1111/j.1348-0421.2012.12005.x

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  • 12-Methyltetradecanoic Acid, a Branched-Chain Fatty Acid, Represses the Extracellular Production of Surfactants Required for Swarming Motility in Pseudomonas aeruginosa PAO1 Reviewed

    Tetsuyoshi Inoue, Teruo Kuroda, Naoya Ohara

    JAPANESE JOURNAL OF INFECTIOUS DISEASES   65 ( 2 )   126 - 131   2012.3

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  • Lipid Phenotype of Two Distinct Subpopulations of Mycobacterium bovis Bacillus Calmette-Guerin Tokyo 172 Substrain Reviewed

    Takashi Naka, Shinji Maeda, Mamiko Niki, Naoya Ohara, Saburo Yamamoto, Ikuya Yano, Jun-ichi Maeyama, Hisashi Ogura, Kazuo Kobayashi, Nagatoshi Fujiwara

    JOURNAL OF BIOLOGICAL CHEMISTRY   286 ( 51 )   44153 - 44161   2011.12

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    DOI： 10.1074/jbc.M111.310037

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  • Effects of non-iron metalloporphyrins on growth and gene expression of Porphyromonas gingivalis Reviewed

    Hideharu Yukitake, Mariko Naito, Keiko Sato, Mikio Shoji, Naoya Ohara, Mamiko Yoshimura, Eiko Sakai, Koji Nakayama

    MICROBIOLOGY AND IMMUNOLOGY   55 ( 3 )   141 - 153   2011.3

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    DOI： 10.1111/j.1348-0421.2010.00299.x

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  • Tetratricopeptide Repeat Protein-Associated Proteins Contribute to the Virulence of Porphyromonas gingivalis Reviewed

    Yoshio Kondo, Naoya Ohara, Keiko Sato, Mamiko Yoshimura, Hideharu Yukitake, Mariko Naito, Taku Fujiwara, Koji Nakayama

    INFECTION AND IMMUNITY   78 ( 6 )   2846 - 2856   2010.6

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    DOI： 10.1128/IAI.01448-09

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  • Suppressed induction of mycobacterial antigen-specific T(h)1-type CD4(+) T cells in the lung after pulmonary mycobacterial infection Reviewed

    Ayano Yahagi, Masayuki Umemura, Toshiki Tamura, Ai Kariyone, M. Dilara Begum, Kazuyoshi Kawakami, Yuko Okamoto, Satoru Hamada, Kiyotetsu Oshiro, Hideyasu Kohama, Takeshi Arakawa, Naoya Ohara, Kiyoshi Takatsu, Goro Matsuzaki

    INTERNATIONAL IMMUNOLOGY   22 ( 4 )   307 - 318   2010.4

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    DOI： 10.1093/intimm/dxq010

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  • ATP測定法を用いた歯科医師着用の歯科用ゴーグルと眼鏡の清浄度調査

    佐藤 法仁, 渡辺 朱理, 苔口 進, 大原 直也

    日本環境感染学会誌   25 ( 2 )   79 - 84   2010.3

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  • Investigation of Contamination on Dental Surgical Goggles and Protective Spectacles by ATP Measuring Method Reviewed

    Norito Satoh, Akari Watanabe, Susumu Kokeguchi, Naoya Ohara

    Japanese Journal of Environmental Infections   25 ( 2 )   79 - 84   2010

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    DOI： 10.4058/jsei.25.79

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  • Hydrogen Sulfide Production From Cysteine and Homocysteine by Periodontal and Oral Bacteria Reviewed

    Akihiro Yoshida, Mamiko Yoshimura, Naoya Ohara, Shigeru Yoshimura, Shiori Nagashima, Tadamichi Takehara, Koji Nakayama

    JOURNAL OF PERIODONTOLOGY   80 ( 11 )   1845 - 1851   2009.11

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    DOI： 10.1902/jop.2009.090012

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  • Porphyromonas gingivalis mutant defective in a putative extracytoplasmic function sigma factor shows a mutator phenotype Reviewed

    Y. Kikuchi, N. Ohara, O. Ueda, K. Hirai, Y. Shibata, K. Nakayama, S. Fujimura

    ORAL MICROBIOLOGY AND IMMUNOLOGY   24 ( 5 )   377 - 383   2009.10

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  • Proteome analysis of Porphyromonas gingivalis cells placed in a subcutaneous chamber of mice Reviewed

    M. Yoshimura, N. Ohara, Y. Kondo, M. Shoji, S. Okano, Y. Nakano, Y. Abiko, K. Nakayama

    ORAL MICROBIOLOGY AND IMMUNOLOGY   23 ( 5 )   413 - 418   2008.10

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  • Determination of the Genome Sequence of Porphyromonas gingivalis Strain ATCC 33277 and Genomic Comparison with Strain W83 Revealed Extensive Genome Rearrangements in P-gingivalis Reviewed

    Mariko Naito, Hideki Hirakawa, Atsushi Yamashita, Naoya Ohara, Mikio Shoji, Hideharu Yukitake, Keisuke Nakayama, Hidehiro Toh, Fuminobu Yoshimura, Satoru Kuhara, Masahira Hattori, Tetsuya Hayashi, Koji Nakayama

    DNA RESEARCH   15 ( 4 )   215 - 225   2008.8

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    DOI： 10.1093/dnares/dsn013

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  • Efficacy of recombinant bacille Calmette-Guerin vaccine secreting interleukin-15/antigen 85B fusion protein in providing protection against Mycobacterium tuberculosis Reviewed

    Ce Tang, Hisakata Yamada, Kensuke Shibata, Naoyoshi Maeda, Shinichi Yoshida, Worawidh Wajjwalku, Naoya Ohara, Takeshi Yamada, Taroh Kinoshita, Yasunobu Yoshikai

    JOURNAL OF INFECTIOUS DISEASES   197 ( 9 )   1263 - 1274   2008.5

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    DOI： 10.1086/586902

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  • Evidence for association between a Toll-like receptor 4 gene polymorphism and moderate/severe periodontitis in the Japanese population Reviewed

    T. Fukusaki, N. Ohara, Y. Hara, A. Yoshimura, K. Yoshiura

    JOURNAL OF PERIODONTAL RESEARCH   42 ( 6 )   541 - 545   2007.12

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    DOI： 10.1111/j.1600-0765.2007.00979.x

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  • Molecular analysis of RANKL-independent cell fusion of osteoclast-like cells induced by TNF-alpha, lipopolysaccharide, or peptidoglycan. Reviewed International journal

    Hitoshi Hotokezaka, Eiko Sakai, Naoya Ohara, Yuka Hotokezaka, Carmen Gonzales, Ken-ichiro Matsuo, Yuji Fujimura, Noriaki Yoshida, Koji Nakayama

    Journal of cellular biochemistry   101 ( 1 )   122 - 34   2007.5

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    DOI： 10.1002/jcb.21167

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  • The hemoglobin receptor protein of porphyromonas gingivalis inhibits receptor activator NF-kappaB ligand-induced osteoclastogenesis from bone marrow macrophages. Reviewed International journal

    Yuji Fujimura, Hitoshi Hotokezaka, Naoya Ohara, Mariko Naito, Eiko Sakai, Mamiko Yoshimura, Yuka Narita, Hideki Kitaura, Noriaki Yoshida, Koji Nakayama

    Infection and immunity   74 ( 5 )   2544 - 51   2006.5

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    Extracellular proteinaceous factors of Porphyromonas gingivalis, a periodontal pathogen, that influence receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced osteoclastogenesis from bone marrow macrophages were investigated. The culture supernatant of P. gingivalis had the ability to inhibit RANKL-induced in vitro osteoclastogenesis. A major protein of the culture supernatant, hemoglobin receptor protein (HbR), suppressed RANKL-induced osteoclastogenesis in a dose-dependent fashion. HbR markedly inhibited RANKL-induced osteoclastogenesis when present in the culture for the first 24 h after addition of RANKL, whereas no significant inhibition was observed when HbR was added after 24 h or later, implying that HbR might interfere with only the initial stage of RANKL-mediated differentiation. HbR tightly bound to bone marrow macrophages and had the ability to induce phosphorylation of ERK, p38, NF-kappaB, and Akt. RANKL-induced phosphorylation of ERK, p38, and NF-kappaB was not suppressed by HbR, but that of Akt was markedly suppressed. HbR inhibited RANKL-mediated induction of c-Fos and NFATc1. HbR could induce beta interferon (IFN-beta) from bone marrow macrophages, but the induction level of IFN-beta might not be sufficient to suppress RANKL-mediated osteoclastogenesis, implying presence of an IFN-beta-independent pathway in HbR-mediated inhibition of osteoclastogenesis. Since rapid and extensive destruction of the alveolar bone causes tooth loss, resulting in loss of the gingival crevice that is an anatomical niche for periodontal pathogens such as P. gingivalis, the suppressive effect of HbR on osteoclastogenesis may help the microorganism exist long in the niche.

    DOI： 10.1128/IAI.74.5.2544-2551.2006

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  • Superoxide dismutase-encoding gene of the obligate anaerobe Porphyromonas gingivalis is regulated by the redox-sensing transcription activator OxyR Reviewed

    N Ohara, Y Kikuchi, M Shoji, M Naito, K Nakayama

    MICROBIOLOGY-SGM   152 ( Pt 4 )   955 - 966   2006.4

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    DOI： 10.1099/mic.0.28537-0

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  • Mutant Escherichia coli enterotoxin as a mucosal adjuvant induces specific Th1 responses of CD4(+) and CD8(+) T cells to nasal killed-bacillus calmette-guerin in mice Reviewed

    H Takahashi, K Sasaki, M Takahashi, N Shigemori, S Honda, H Arimitsu, S Ochi, N Ohara, T Tsuji

    VACCINE   24 ( 17 )   3591 - 3598   2006.4

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    DOI： 10.1016/j.vaccine.2006.01.060

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  • Dissecting the role of Rho-mediated signaling in contractile ring Formation Reviewed

    K Kamijo, N Ohara, M Abe, T Uchimura, H Hosoya, JS Lee, T Miki

    MOLECULAR BIOLOGY OF THE CELL   17 ( 1 )   43 - 55   2006.1

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    DOI： 10.1091/mbc.e05-06-0569

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  • Porphyromonas gingivalis-induced platelet aggregation in plasma depends on Hgp44 adhesin but not Rgp proteinase Reviewed

    M Naito, E Sakai, YX Shi, H Ideguchi, M Shoji, N Ohara, K Yamamoto, K Nakayama

    MOLECULAR MICROBIOLOGY   59 ( 1 )   152 - 167   2006.1

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    DOI： 10.1111/j.1365-2958.2005.04942.x

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  • Analysis of amphotericin B-induced cell signaling with chemical inhibitors of signaling molecules. Reviewed International journal

    Kenichiro Matsuo, Hitoshi Hotokezaka, Naoya Ohara, Yuji Fujimura, Atsutoshi Yoshimura, Yukio Okada, Yoshitaka Hara, Noriaki Yoshida, Koji Nakayama

    Microbiology and immunology   50 ( 4 )   337 - 47   2006

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    Although amphotericin B (AmB) is a major polyene antibiotic against invasive fungal infection, administration to patients sometimes causes inflammatory side effects, which limits the usage of the antibiotic. We studied the intracellular signaling that was induced by AmB. p65 (RelA) of nuclear factor-kappaB (NF-kappaB), a well-known signaling molecule as an inducer of proinflammatory cytokines, was phosphorylated by AmB in RAW264.7 cells, a monocyte-like cell line. Among chemical inhibitors of signaling molecules, U-73122 (phospholipase C (PLC) inhibitor), Gö6976 (protein kinase C (PKC) inhibitor), BAPTA-AM (calcium chelator), LFM-A13 (Bruton's tyrosine kinase (Btk)-specific inhibitor), and PP2 (c-Src kinase inhibitor) suppressed AmB-induced phosphorylation of p65 and translocation of p65 into the nucleus. U-73122 and Gö6976 reduced AmB-mediated induction of proinflammatory cytokines (tumor necrosis factor (TNF)-alpha and interleukin (IL)-6) in RAW264.7 cells. Furthermore, AmB-induced activation of NF-kappaB was observed in toll-like receptor (TLR) 2-expressed cells, and the activation of NF-kappaB was inhibited by U-73122, whereas peptidoglycan-induced NF-kappaB activation, which was also dependent on TLR2, was not inhibited by U-73122. Finally, U-73122 partially suppressed in vivo production of TNF-alpha and IL-6 induced by AmB administration in BALB/c mice. These results suggested that the signaling from AmB stimulation to proinflammatory cytokine production is mediated by TLR2, Btk, PLC, PKC, c-Src and NF-kappaB. These signaling molecules may become a target for chemotherapy suppressing AmB-induced proinflammatory cytokine production.

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  • [Study on antigenicity and pathogenicity of mycobacteria]. Reviewed

    Ohara N

    Nihon saikingaku zasshi. Japanese journal of bacteriology   60 ( 2 )   349 - 356   2005.5

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  • Identification of a new membrane-associated protein that influences transport/maturation of gingipains and adhesins of Porphyromonas gingivalis Reviewed

    K Sato, E Sakai, PD Veith, M Shoji, Y Kikuchi, H Yukitake, N Ohara, M Naito, K Okamoto, EC Reynolds, K Nakayama

    JOURNAL OF BIOLOGICAL CHEMISTRY   280 ( 10 )   8668 - 8677   2005.3

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    DOI： 10.1074/jbc.M413544200

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  • Novel stationary-phase-upregulated protein of Porphyromonas gingivalis influences production of superoxide dismutase, thiol peroxidase and thioredoxin Reviewed

    Y Kikuchi, N Ohara, K Sato, M Yoshimura, H Yukitake, E Sakai, M Shoji, M Naito, K Nakayama

    MICROBIOLOGY-SGM   151 ( Pt 3 )   841 - 853   2005.3

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    DOI： 10.1099/mic.0.27589-0

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  • Novel recombinant BCG and DNA-vaccination against tuberculosis in a cynomolgus monkey Reviewed

    Y Kita, T Tanaka, S Yoshida, N Ohara, Y Kaneda, S Kuwayama, Y Muraki, N Kanamaru, S Hashimoto, H Takai, C Okada, Y Fukunaga, Y Sakaguchi, IN Furukawa, K Yamada, Y Inoue, Y Takemoto, M Naito, T Yamada, M Matsumoto, DN McMurray, EC Dela Cruz, EV Tan, RM Abalos, JA Burgos, R Gelber, Y Skeiky, S Reed, M Sakatani, M Okada

    VACCINE   23 ( 17-18 )   2132 - 2135   2005.3

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    DOI： 10.1016/j.vaccine.2005.01.057

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  • The major structural components of two cell surface filaments of Porphyromonas gingivalis are matured through lipoprotein precursors Reviewed

    M Shoji, M Naito, H Yukitake, K Sato, E Sakai, N Ohara, K Nakayama

    MOLECULAR MICROBIOLOGY   52 ( 5 )   1513 - 1525   2004.6

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    DOI： 10.1111/j.1365-2958.2004.04105.x

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  • Infection-induced up-regulation of the costimulatory molecule 4-1BB in osteoblastic cells and its inhibitory effect on M-CSF/RANKL-induced in vitro osteoclastogenesis. Reviewed International journal

    Kan Saito, Naoya Ohara, Hitoshi Hotokezaka, Satoshi Fukumoto, Kenji Yuasa, Mariko Naito, Taku Fujiwara, Koji Nakayama

    The Journal of biological chemistry   279 ( 14 )   13555 - 63   2004.4

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    Bacterial infection sometimes impairs bone metabolism. In this study, we infected the osteoblastic cell line MC3T3-E1 with Mycobacterium bovis bacillus Calmette-Guérin (BCG) and identified genes that were up-regulated in the BCG-infected cells by the suppression subtractive hybridization method. A gene encoding 4-1BB (CD137), a member of the tumor necrosis factor-alpha receptor family, was found to be one of the up-regulated genes. Up-regulation of 4-1BB was also observed by infection with Escherichia coli, Salmonella typhimurium, and Staphylococcus aureus, and by treatment with lipopolysaccharides and heat-killed BCG. Bone marrow cells and the macrophage-like cell lines J774 and RAW264.7 were found to express 4-1BB ligand (4-1BBL). Recombinant 4-1BB (r4-1BB) that was immobilized on culture plates strongly inhibited macrophage colony stimulating factor (M-CSF)/receptor activator of nuclear factor-kappaB ligand (RANKL)-induced in vitro osteoclast formation from bone marrow cells. Anti-4-1BBL antibody also inhibited osteoclast formation to a lesser extent, indicating involvement of reverse signaling through 4-1BBL during inhibition of osteoclast formation. A casein kinase I (CKI) inhibitor markedly suppressed the inhibitory effect of r4-1BB on M-CSF/RANKL-induced osteoclast formation, suggesting that CKI might be involved in 4-1BB/4-1BBL reverse signaling. r4-1BB showed no effects on M-CSF- or RANKL-induced phosphorylation of I-kappaB, ERK1/2, p38, or JNK, whereas RANKL-induced phosphorylation of Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K), was completely abolished by r4-1BB, suggesting that 4-1BB/4-1BBL reverse signaling may interfere with PI3K/Akt pathway. r4-1BB also abolished RANKL-mediated induction of nuclear factor of activated T cells-2. This study may elucidate a novel role of 4-1BB in cell metabolism, especially osteoclastogenesis.

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  • Induction of protective cellular immunity against Mycobacterium tuberculosis by recombinant attenuated self-destructing Listeria monocytogenes strains harboring eukaryotic expression plasmids for antigen 85 complex and MPB/MPT51 Reviewed

    K Miki, T Nagata, T Tanaka, YH Kim, M Uchijima, N Ohara, S Nakamura, M Okada, Y Koide

    INFECTION AND IMMUNITY   72 ( 4 )   2014 - 2021   2004.4

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  • Deregulation and mislocalization of the cytokinesis regulator ECT2 activate the Rho signaling pathways leading to malignant transformation Reviewed

    S Saito, XF Liu, K Kamijo, R Raziuddin, T Tatsumoto, Okamoto, I, XY Chen, CC Lee, MV Lorenzi, N Ohara, T Miki

    JOURNAL OF BIOLOGICAL CHEMISTRY   279 ( 8 )   7169 - 7179   2004.2

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  • MgcRacGAP regulates cortical activity through RhoA during cytokinesis Reviewed

    JS Lee, K Kamijo, N Ohara, T Kitamura, T Miki

    EXPERIMENTAL CELL RESEARCH   293 ( 2 )   275 - 282   2004.2

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  • Novel (recombinant BCG- and DNA-) vaccination against tuberculosis using cynomolgus monkey Reviewed

    Kita, I, T Tanaka, S Yoshida, N Ohara, Y Kaneda, Kuwayama, I, Muraki, I, Kanamaru, I, S Hashimoto, H Takai, C Okada, Y Fukunaga, Y Sakaguchi, Furukawa, I, K Yamada, Inoue, I, Takemoto, I, M Naito, T Yamada, M Matsumoto, EC Cruz, EV Tan, RM Abalos, LJ Young, JA Burgos, R Gelber, Y Skeiky, S Reed, M Sakatani, M Okada

    IMMUNOLOGY 2004: IMMUNODEFICIENCY, INFECTIOUS DISEASES, IMMUNOMODULATION, AND VACCINES   403 - 406   2004

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  • Changed activation of HIV-1 LTR in monocytoid cells by mycobacteria with temporal progression of infection Reviewed

    H Kitaura, N Ohara, N Nakao, N Yoshida, T Yamada

    MICROBIOLOGICA   25 ( 3 )   357 - 361   2002.7

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  • Discovery of immunostimulatory CpG-DNA and its application to tuberculosis vaccine development Reviewed

    S Yamamoto, T Yamamoto, Y Nojima, K Umemori, S Phalen, DN McMurray, E Kuramoto, S Iho, R Takauji, Y Sato, T Yamada, N Ohara, S Matsumoto, Y Goto, K Matsuo, T Tokunaga

    JAPANESE JOURNAL OF INFECTIOUS DISEASES   55 ( 2 )   37 - 44   2002.4

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  • Expression of alkaline phosphatase induces rapid and artificial mineralization in specific transformed Escherichia coli Reviewed

    N Ohara, N Ohara, K Yanagiguchi, S Yamada, IL Viloria, Y Hayashi

    MICROBIOLOGICA   25 ( 1 )   107 - 110   2002.1

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  • TNF-alpha-mediated activation of HIV-1 LTR in monocytoid cells by mycobacteria Reviewed

    H Kitaura, N Ohara, K Kobayashi, T Yamada

    FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY   31 ( 2 )   97 - 103   2001.8

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  • Recombinant BCG vaccines Invited Reviewed

    N Ohara, T Yamada

    VACCINE   19 ( 30 )   4089 - 4098   2001.7

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  • TNF-alpha-mediated multiplication of human immunodeficiency virus in chronically infected monocytoid cells by mycobacterial infection Reviewed

    H Kitaura, N Ohara, K Kobayashi, T Yamada

    APMIS   109 ( 7-8 )   533 - 540   2001.7

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  • Protective responses against experimental Mycobacterium leprae infection in mice induced by recombinant Bacillus Calmette-Guerin over-producing three putative protective antigen candidates Reviewed

    N Ohara, M Matsuoka, H Nomaguchi, M Naito, T Yamada

    VACCINE   19 ( 15-16 )   1906 - 1910   2001.2

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  • Identification and characterization of the ribosome-associated protein, HrpA, of Bacillus Calmette-Guerin Reviewed

    Y Tabira, N Ohara, T Yamada

    MICROBIAL PATHOGENESIS   29 ( 4 )   213 - 222   2000.10

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    DOI： 10.1006/mpat.2000.0384

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  • Fibronectin-binding proteins secreted by Mycobacterium avium Reviewed

    H Kitaura, N Ohara, M Naito, K Kobayashi, T Yamada

    APMIS   108 ( 9 )   558 - 564   2000.9

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  • Inhibition of multiplication of Mycobacterium leprae in mouse foot pads by recombinant Bacillus Catmette-Guerin (BCG) Reviewed

    N Ohara, M Matsuoka, H Nomaguchi, M Naito, T Yamada

    VACCINE   18 ( 14 )   1294 - 1297   2000.1

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  • The antigen 85 complex vaccine against experimental Mycobacterium leprae infection in mice Reviewed

    M Naito, M Matsuoka, N Ohara, H Nomaguchi, T Yamada

    VACCINE   18 ( 9-10 )   795 - 798   1999.12

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  • Species-specific B-cell epitope on the C-terminal region of the alpha antigen from Mycobacterium intracellulare in mice Reviewed

    H Kitaura, N Ohara, M Naito, K Kobayashi, T Yamada

    VETERINARY MICROBIOLOGY   65 ( 1 )   9 - 19   1999.2

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  • Host immune responses to ribosome, ribosomal proteins, and RNA from Mycobacterium bovis bacille de Calmette-Guerin Reviewed

    C Miyazaki, N Ohara, H Yukitake, M Kinomoto, K Matsushita, S Matsumoto, A Mizuno, T Yamada

    VACCINE   17 ( 3 )   245 - 251   1999.1

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  • Serological analysis of C-terminal region of alpha antigen from Mycobacterium avium-intracellulare complex and Mycobacterium tuberculosis Reviewed

    H Kitaura, N Ohara, M Naito, K Kobayashi, T Yamada

    APMIS   106 ( 9 )   893 - 900   1998.9

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  • Immunological characterization of alpha antigen of Mycobacterium kansasii: B-cell epitope mapping Reviewed

    M Naito, N Ohara, S Matsumoto, T Yamada

    SCANDINAVIAN JOURNAL OF IMMUNOLOGY   48 ( 1 )   73 - 78   1998.7

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  • The 16-kDa alpha-crystallin-like protein of Mycobacterium bovis BCG is produced under conditions of oxygen deficiency and is associated with ribosomes Reviewed

    Y Tabira, N Ohara, N Ohara, H Kitaura, S Matsumoto, M Naito, T Yamada

    RESEARCH IN MICROBIOLOGY   149 ( 4 )   255 - 264   1998.4

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  • Differentiation of clinical isolates of Actinobacillus actinomycetemcomitans using an insertion sequence, ISAa1. Reviewed International journal

    H Hayashida, H Hotokezaka, N Ohara, T Koseki, T Nishihara, O Takagi, T Yamada

    Oral microbiology and immunology   13 ( 2 )   120 - 3   1998.4

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    We previously identified an IS200-like sequence (ISAa1) in the genome of Actinobacillus actinomycetemcomitans FDC Y4. One or more hybridizing bands to the ISAa1 probe were detected in each of several reference strains, representing three of the serotypes (a through c) of A. actinomycetemcomitans. In this study, we examined whether a restriction fragment-length polymorphism (RFLP) with ISAa1 as a probe could differentiate clinical isolates. One or more hybridizing bands were detected in each of the 27 strains examined, which could be divided into seven groups according to restriction fragment-length polymorphism pattern. Several strains were observed with identical restriction fragment-length polymorphism types but with different serotypes. Conversely, strains were also observed with differing restriction fragment-length polymorphism types and identical serotypes.

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  • The novel fibronectin-binding motif and key residues of mycobacteria Reviewed

    M Naito, N Ohara, S Matsumoto, T Yamada

    JOURNAL OF BIOLOGICAL CHEMISTRY   273 ( 5 )   2905 - 2909   1998.1

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  • The ribosomes contents of mycobacteria Reviewed

    T Mineda, N Ohara, H Yukitake, T Yamada

    MICROBIOLOGICA   21 ( 1 )   1 - 7   1998.1

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  • PCR amplification of 16S ribosomal RNA gene for detection of bacterial infection in root canal Reviewed

    Dentistry in Japan   34   21 - 23   1998

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  • Shotgun cloning and characterization of the thymidylate synthase-encoding gene from Mycobacterium bovis BCG Reviewed

    S Matsumoto, H Yukitake, N Ohara, T Dairi, H Kanbara, T Yamada

    MICROBIOLOGY AND IMMUNOLOGY   42 ( 1 )   15 - 21   1998

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  • Characterization of the transcriptional initiation regions of genes for the major secreted protein antigens 85C and MPB51 of Mycobacterium bovis BCG Reviewed

    N Ohara, T Nishiyama, N Ohara-Wada, S Matsumoto, T Matsuo, T Yamada

    MICROBIAL PATHOGENESIS   23 ( 5 )   303 - 310   1997.11

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  • HrpA, a new ribosome-associated protein which appears in heat-stressed Mycobacterium bovis Bacillus Calmette-Guerin Reviewed

    N Ohara, N Ohara, M Naito, C Miyazaki, S Matsumoto, Y Tabira, T Yamada

    JOURNAL OF BACTERIOLOGY   179 ( 20 )   6495 - 6498   1997.10

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  • Analysis of the genes encoding the antigen 85 complex and MPT51 from Mycobacterium avium Reviewed

    N Ohara, N OharaWada, H Kitaura, T Nishiyama, S Matsumoto, T Yamada

    INFECTION AND IMMUNITY   65 ( 9 )   3680 - 3685   1997.9

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  • Transcriptional analysis of the groESL operon from Porphyromonas gingivalis. Reviewed International journal

    H Hotokezaka, N Ohara, H Hayashida, S Matsumoto, T Matsuo, M Naito, K Kobayashi, T Yamada

    Oral microbiology and immunology   12 ( 4 )   236 - 9   1997.8

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    Transcriptional analysis of the groESL operon from Porphyromonas gingivalis, one of the obligative anaerobic oral microorganisms implicated in adult periodontitis, was performed. P. gingivalis 381 cultured at 37 degrees C was shifted to 42 degrees C, 45 degrees C or 48 degrees C for 10 mins. Northern hybridization analysis revealed that a band with 2.1-kb (kilo base pair) was observed, and the transcripts increased greatly by heat shock. Primer extension and S1 mapping detected four different 5'-ending sites of the mRNAs at the upstream region of the groES. Three sites out of the four were heat-inducible. There were inverted repeats and a Escherichia coli sigma 32-recognizing consensus sequence in the promoter region of the groESL, which may be relevant to the regulation of transcription of groESL operon in P. gingivalis. Both a heat shock promoter and inverted repeats may be relevant to the transcriptional regulation of the groESL operon in P. gingivalis.

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  • Inhibition of multiplication of Mycobacterium leprae in mouse foot pads by immunization with ribosomal fraction and culture filtrate from Mycobacterium bovis BCG Reviewed

    M Matsuoka, H Nomaguchi, H Yukitake, N Ohara, S Matsumoto, K Mise, T Yamada

    VACCINE   15 ( 11 )   1214 - 1217   1997.8

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  • Species-specific B-cell epitope on the C-terminal region of the alpha antigen from Mycobacterium scrofulaceum Reviewed

    M Takano, N Ohara, M Naito, S Matsumoto, T Matsuo, R Shirai, A Mizuno, T Yamada

    MICROBIAL PATHOGENESIS   23 ( 2 )   95 - 100   1997.8

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  • Cloning and sequencing of part of the S10 operon from Actinobacillus actinomycetemcomitans FDC Y4. Reviewed International journal

    H Hayashida, H Hotokezaka, N Ohara, M Kimura, O Takagi, T Yamada

    Oral microbiology and immunology   12 ( 3 )   174 - 7   1997.6

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    We have cloned and sequenced the 5.2 kb EcoRI fragment that contained part of the S10 operon from Actinobacillus actinomycetemcomitans FDC Y4. The order of the ribosomal protein genes was identical to that of the S10 operon of Haemophilus influenzae and Escherichia coli. The deduced amino acid sequences of ribosomal proteins in this operon displayed significant homologies (65.3%-100%) to those of H. influenzae, E. coli, Yersinia enterocolitica and Yersinia pseudotuberculosis. Phylogenetic trees obtained for these ribosomal proteins were similar to that obtained for 16S rRNA.

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  • Molecular analysis of a new insertion sequence from Actinobacillus (Haemophilus) actinomycetemcomitans FDC Y4. Reviewed International journal

    H Hayashida, H Hotokezaka, N Ohara, M Kimura, O Takagi, T Yamada

    Microbiology (Reading, England)   142 ( Pt 9)   2449 - 52   1996.9

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    We have found a new insertion sequence (IS), designated ISAa1, downstream of the S10 operon in Actinobacillus (Haemophilus) actinomycetemcomitans FDC Y4. ISAa1, the first IS element characterized in this organism, is 705 bp long and lacks terminal inverted repeats. This element displayed significant homology with IS200. Hybridization patterns of genomic DNA of seven A. actinomycetemcomitans strains with an internal ISAa1 probe varied depending on the serotypes, suggesting that ISAa1 might be a useful tool for epidemiological studies.

    DOI： 10.1099/00221287-142-9-2449

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  • BCG Vaccunation to Mycobacterium leprae Infection in Mice

    NOMAGUCHI Hiroko, YOGI Yasuko, MATSUOKA Masanori, FUKUTOMI Yasuo, OKAMURA Haruki, NAGATA Kumiko, NAGAI Sadamu, OHARA Naoya, YAMADA Tsuyoshi

    Japanese journal of leprosy   65 ( 2 )   106 - 112   1996.7

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    BCG vaccine (Tokyo strain) was given in BALB/cA mice intradermally 1 or 3 months before Mycobacterium leprae (M. leprae) challenge as modified Shepard's method. The vaccine dosage was 7-8 or 106. The BCG gave good protection in both dosages and both challenges against M. leprae infection.<br>Lymphocytes proliferations of BCG-vaccinated splenocyte cultures in response to M. leprae lysate or BCG components (hsp65, 38kD, 30kD or 12kD protein) were tested, and potent proliferative responses were seen in the cultures with M. leprae lysate and hsp 65. Furthermore, γ-IFN productions were positive in the cultures with M. leprae lysate or hsp 65, but negative with other antigens. The production of γ-IFN with hsp 65 was never inhibited with polymyxin B, but inhibited with IL-10.<br>These results show that BCG (Tokyo strain) is a useful vaccine for M. leprae infection in mice, and one of the components of BCG, hsp 65, may be a effective antigen component for protection of M. leprae infection inducing Thl type cytokine.

    DOI： 10.5025/hansen.65.106

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  • Cloning and sequencing of an MPB70 homologue corresponding to MPB83 from Mycobacterium bovis BCG Reviewed

    T Matsuo, H Matsuo, N Ohara, S Matsumoto, H Kitaura, A Mizuno, T Yamada

    SCANDINAVIAN JOURNAL OF IMMUNOLOGY   43 ( 5 )   483 - 489   1996.5

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  • Long-lasting immune response induced by recombinant Bacillus Calmette-Guerin (BCG) secretion system Reviewed

    N Wada, N Ohara, M Kameoka, Y Nishino, S Matsumoto, T Nishiyama, M Naito, H Yukitake, Y Okada, K Ikuta, T Yamada

    SCANDINAVIAN JOURNAL OF IMMUNOLOGY   43 ( 2 )   202 - 209   1996.2

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  • Stable expression and secretion of the B-cell epitope of rodent malaria from Mycobacterium bovis BCG and induction of long-lasting humoral response in mouse Reviewed

    S Matsumoto, T Yanagi, N Ohara, N Wada, H Kanbara, T Yamada

    VACCINE   14 ( 1 )   54 - 60   1996.1

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  • BCG vaccination to Mycobacterium leprae infection in mice Reviewed

    H. Nomaguchi, Y. Fukutomi, S. Nagai, Y. Yogi, H. Okamura, N. Ohara, Matsuoka M, K. Nagata, T. Yamada

    Japanese Journal of Leprosy   65 ( 2 )   106 - 112   1996

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  • AN INTERNAL CONTROL FOR THE RAPID DETECTION OF MYCOBACTERIA BY AMPLIFICATION OF A SEGMENT OF THE GENE ENCODING ALPHA-ANTIGEN Reviewed

    H KITAURA, N OHARA, T MATSUO, T YAMADA

    MICROBIOLOGICA   18 ( 4 )   429 - 433   1995.10

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  • DIFFERENTIAL TRANSCRIPTION OF THE MPB70 GENES IN 2 MAJOR GROUPS OF MYCOBACTERIUM-BOVIS BCG SUBSTRAINS Reviewed

    T MATSUO, S MATSUMOTO, N OHARA, H KITAURA, A MIZUNO, T YAMADA

    MICROBIOLOGY-UK   141   1601 - 1607   1995.7

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    DOI： 10.1099/13500872-141-7-1601

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  • Characterization of the gene encoding the MPB51, one of the major secreted protein antigens of Mycobacterium bovis BCG, and identification of the secreted protein closely related to the fibronectin binding 85 complex. Reviewed International journal

    N Ohara, H Kitaura, H Hotokezaka, T Nishiyama, N Wada, S Matsumoto, T Matsuo, M Naito, T Yamada

    Scandinavian journal of immunology   41 ( 5 )   433 - 42   1995.5

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    The secreted protein MPB51 is one of the major proteins in the culture filtrate of Mycobacterium bovis BCG (BCG) and is a protein immunologically cross-reacting with the fibronectin binding 85 complex secreted by this bacterium. The gene encoding MPB51 (mpb51) was cloned, sequenced, and expressed in Escherichia coli. The mpb51 gene was mapped downstream of the gene for 85A component with 179 bp spaces. The mpb51 gene encoded 299 amino acids, including 33 amino acids for the signal peptide, followed by 266 amino acids for the mature protein with a molecular mass of 27807.37 Da. This is the first complete sequence of MPB51. MPB51 showed 37-43% homology to the components of 85 complex. Two-dimensional electrophoresis of culture fluids of BCG and Western blotting indicated the existence of the other novel protein(s) which strongly cross-reacted with the alpha antigen (85B) and MPB51.

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  • CLONING AND NUCLEOTIDE-SEQUENCE OF THE GENE-CLUSTER ENCODING RIBOSOMAL-PROTEINS S12 AND S7 FROM MYCOBACTERIUM-BOVIS BCG Reviewed

    S IWANAGA, N OHARA, T KARIU, M KIMURA, N YAMASAKI, T YAMADA

    BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL   36 ( 1 )   209 - 218   1995.5

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  • Cloning and sequencing of a unique antigen MPT70 from Mycobacterium tuberculosis H37Rv and expression in BCG using E. coli-mycobacteria shuttle vector. Reviewed International journal

    S Matsumoto, T Matsuo, N Ohara, H Hotokezaka, M Naito, J Minami, T Yamada

    Scandinavian journal of immunology   41 ( 3 )   281 - 7   1995.3

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    MPB70 is known to be an immunogenic mycobacterial protein secreted in large amounts from Mycobacterium bovis BCG (BCG) Tokyo. The analogous gene for MPT70 was cloned from Mycobacterium tuberculosis H37Rv which produces this protein in only a small amount. The gene encoding 193 amino acid residues including 30 amino acids for the signal peptide, the promoter-like sequence, and the ribosome-binding site, was completely identical to that of BCG Tokyo. Computer analysis revealed that the carboxy-terminal half of MPT70 was homologous to amino acid sequences of fasciclin I, osteoblast-specific factor 2 (OSF-2), and human transforming growth factor-beta induced gene product (beta IG-H3). Escherichia coli (E. coli) -mycobacteria shuttle vectors containing mpt70 or mpb70 genes 0.7kbp upstream of the 5' end of them were able to be expressed in BCG Pasteur which is a MPB70 low-producer, but the extent of the expression was not that of a high-producer.

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  • 1. The role of some cellular components of bacterial parasites in determining the incidence of tuberculosis: Studies on mycobacterial antigens, with special reference to mycobacterial immunoreactive ribosomal and secreted proteins Reviewed

    T. Yamada, N. Ohara, S. Matsumoto, T. Matsuo, H. Kitaura, H. Yukitake, N. Wada, T. Nishiyama, M. Naito, M. Kinomoto, M. Kimura

    Kekkaku   70 ( 11 )   639 - 644   1995

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  • Biochemical and Immunological Characterization of Ribosomal Fraction and Culture Filtrate from Mycobacterium Reviewed

    Yamada T, Ohara N, Wada N, Matsumoto S, Yukitake E, Matsuo T, Kitaura H, Takano M, Nishiyama T, Nomaguchi H, Matsuo M

    Actinomycetol   9 ( 2 )   228 - 235   1995

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    DOI： 10.3209/saj.9_228

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  • Cloning and sequencing of the groESL homologue from Porphyromonas gingivalis. Reviewed International journal

    H Hotokezaka, H Hayashida, N Ohara, H Nomaguchi, K Kobayashi, T Yamada

    Biochimica et biophysica acta   1219 ( 1 )   175 - 8   1994.9

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    The homologue of groESL from Porphyromonas gingivalis was cloned and sequenced. Nucleotide sequencing suggested an operon containing two open reading frames (ORFs) homologous to groESL operon of Escherichia coli. The upstream ORF consisted of 267 bp corresponding to 89 amino acid residues. The downstream ORF consisted of 1635 bp corresponding to 545 amino acid residues.

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  • Cloning and sequencing of the groESL homologue from Porphyromonas gingivalis

    Hitoshi Hotokezaka, Hideaki Hayashida, Naoya Ohara, Hiroko Nomaguchi, Kazuhide Kobayashi, Takeshi Yamada

    BBA - Gene Structure and Expression   1219   175 - 178   1994.9

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    DOI： 10.1016/0167-4781(94)90265-8

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  • CLONING, SEQUENCING AND EXPRESSION IN ESCHERICHIA-COLI OF THE GENE FOR ALPHA-ANTIGEN FROM MYCOBACTERIUM-SCROFULACEUM Reviewed

    M TAKANO, N OHARA, A MIZUNO, T YAMADA

    SCANDINAVIAN JOURNAL OF IMMUNOLOGY   40 ( 2 )   165 - 170   1994.8

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  • CYTOTOXIC T-LYMPHOCYTE RESPONSE IN MICE INDUCED BY A RECOMBINANT BCG VACCINATION WHICH PRODUCES AN EXTRACELLULAR ALPHA ANTIGEN THAT FUSED WITH THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENVELOPE IMMUNODOMINANT DOMAIN IN THE V3 LOOP Reviewed

    M KAMEOKA, Y NISHINO, K MATSUO, N OHARA, T KIMURA, A YAMAZAKI, T YAMADA, K IKUTA

    VACCINE   12 ( 2 )   153 - 158   1994.2

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  • CLONING, SEQUENCING AND EXPRESSION OF THE GENE FOR ALPHA-ANTIGEN FROM MYCOBACTERIUM-INTRACELLULARE AND USE OF PCR FOR THE RAPID IDENTIFICATION OF MYCOBACTERIUM-INTRACELLULARE Reviewed

    H KITAURA, N OHARA, T MATSUO, H TASAKA, K KOBAYASHI, T YAMADA

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   196 ( 3 )   1466 - 1473   1993.11

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    DOI： 10.1006/bbrc.1993.2417

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  • IMMUNOLOGICAL PROPERTIES OF RIBOSOMAL-PROTEINS FROM MYCOBACTERIUM-BOVIS BCG Reviewed

    S TANTIMAVANICH, S NAGAI, H NOMAGUCHI, M KINOMOTO, N OHARA, T YAMADA

    INFECTION AND IMMUNITY   61 ( 9 )   4005 - 4007   1993.9

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  • ISOLATION AND AMINO-ACID-SEQUENCE OF THE 30S-RIBOSOMAL PROTEIN-S19 FROM MYCOBACTERIUM-BOVIS BCG Reviewed

    N OHARA, M KIMURA, Y HIGASHI, T YAMADA

    FEBS LETTERS   331 ( 1-2 )   9 - 14   1993.9

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  • CLONING AND SEQUENCING OF THE GENE ENCODING THE RIBOSOMAL L7/L12-LIKE PROTEIN OF MYCOBACTERIUM-BOVIS BCG Reviewed

    N OHARA, M KIMURA, N WADA, T YAMADA

    NUCLEIC ACIDS RESEARCH   21 ( 15 )   3579 - 3579   1993.7

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  • CLONING AND SEQUENCING OF THE GENE FOR ALPHA-ANTIGEN FROM MYCOBACTERIUM-AVIUM AND MAPPING OF B-CELL EPITOPES Reviewed

    N OHARA, K MATSUO, R YAMAGUCHI, A YAMAZAKI, H TASAKA, T YAMADA

    INFECTION AND IMMUNITY   61 ( 4 )   1173 - 1179   1993.4

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  • III-2. Study on recombinant BCG Reviewed

    K. Matsuo, R. Yamaguchi, A. Yamazaki, K. Terasaka, S. Nagai, H. Tasaka, C. Abe, M. Totsuka, H. Yukitake, K. Kobayashi, N. Ohara, T. Yamada

    Kekkaku   66 ( 9 )   615 - 619   1991

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  • The comparison of recovery rate and distribution of Brugia pahangi in mogolian jirds (Meriones unguiculatus) kept at different levels of ambient temperature and ultra violet irradiation Reviewed

    Fujiwara M, Ohara N, Shigeno S, Kimura E, Aoki Y

    Trop Med   27 ( 1 )   17 - 22   1985

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Books

  • BCG : TB vaccine : application against tuberculosis and other diseases

    Naoya Ohara（ Role： Contributor ,  Efficacy of BCG vaccination against leprosy and nontuberculous mycobacteria (NTM) infections）

    JATA  2022  （ ISBN:9784874513224 ）

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    Total pages：14, 283 p, 図版 3 p   Language：English

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  • 口腔微生物学・免疫学 第5版

    大原直也（ Role： Joint editor）

    医歯薬出版  2021.11 

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  • シンプル微生物学 改訂第6版

    大原直也（ Role： Contributor）

    南江堂  2018.3  （ ISBN:9784524254835 ）

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  • 結核 改訂版

    大原直也（ Role： Contributor）

    医薬ジャーナル社  2017.7 

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  • 口腔微生物学・免疫学 第4版

    大原直也（ Role： Joint editor）

    医歯薬出版  2016.1  （ ISBN:9784263457917 ）

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  • 非結核性抗酸菌の基礎と臨床

    大原直也,山田毅（ Role： Joint author ,  分子遺伝学的性状）

    医薬ジャーナル社  2015.11  （ ISBN:9784753227273 ）

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    Responsible for pages：141-159   Language：Japanese

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  • レビンソン微生物学・免疫学原書第11版

    大原直也（ Role： Contributor）

    丸善出版  2012.10 

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    Responsible for pages：23-48   Language：Japanese

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  • 免疫の事典

    大原直也（ Role： Contributor）

    朝倉書店  2011.12 

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    Responsible for pages：158, 179, 287, 337   Language：Japanese Book type：Dictionary, encyclopedia

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  • 疾病の成り立ち及び回復過程の促進2 微生物学

    大原直也（ Role： Contributor）

    医歯薬出版  2011.10 

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    Responsible for pages：74-109   Language：Japanese

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  • BCG Vaccine and Adjuvant

    Naoya OHara（ Role： Joint author）

    YATA, Tokyo  2011.5 

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    Responsible for pages：142-152   Language：English

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  • Interface Oral Health Science〈2007〉

    Kondo Y, Yoshimura M, Ohara N, Shoji M, Yukitake H, Naito M, Fujiwara T, Nakayama K（ Role： Joint author）

    Springer  2008  （ ISBN:9784431766896 ）

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    Responsible for pages：271-272   Language：English

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MISC

  • Porphyromonas gingivalis 新規オペロンに存在する Omp 様タンパク質の構造解析と役割

    Chen Yujiang, 武部克希, 佐藤啓子, 中山真彰, 加島佳奈, Zhang Mingzheng, 岡元邦彰, 門脇知子, 大原直也

    Journal of Oral Biosciences Supplement   2024.10

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  • Porphyromonas gingivalis感染におけるホスホリパーゼC活性化による細胞外カルシウムの細胞内流入と歯周 炎の関連性

    中山真彰、内藤真理子、中山浩次、大原直也

    Journal of Oral Biosciences Supplement   2024   2024.10

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  • Porphyromonas gingivalis 感染における PLC を介した細胞内カ ルシウム流入による歯周組織炎症への影響 Reviewed

    中山真彰, 内藤真理子, 中山浩次, 大原直也

    日本細菌学雑誌   79 ( 2 )   189 - 189   2024.6

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  • Porphyromonas gingivalisジンジパインによるphospholipase Cの活性化と歯周組織の炎症との関連性

    中山 真彰, 内藤 真理子, 中山 浩次, 大原 直也

    Journal of Oral Biosciences Supplement   2023   [P3 - 32]   2023.9

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  • Porphyromonas gingivalisジンジパインによるPLCを介したCOX-2発現とPGE2産生の分子機序

    中山 真彰, 山口 智之, 内藤 真理子, 中山 浩次, 大原 直也

    日本細菌学雑誌   78 ( 1 )   88 - 88   2023.2

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  • Mycobacterium avium の酸性環境下での適応能の解析 Reviewed

    瀧井猛将, 伊藤佐生智, 大原直也, 前田伸司, 肥田重明

    日本細菌学雑誌   78 ( 1 )   80 - 80   2023.2

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  • Drug development for drug-resistant tuberculosis and the non-tuberculous mycobacterial disease

    瀧井猛将, 瀧井猛将, 岩月正人, 山口智之, 君嶋葵, 渡邊善行, 中山真彰, 大原直也, 浅見行弘

    日本薬学会年会要旨集(Web)   143rd   2023

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  • Porphyromonas gingivalisジンジパインによるCOX-2発現とPGE2産生におけるホスホリパーゼの役割(The role of phospholipase on Porphyromonas gingivalis gingipains-induced COX-2 expression and PGE2 production)

    中山 真彰, 内藤 真理子, 中山 浩次, 大原 直也

    Journal of Oral Biosciences Supplement   2022   219 - 219   2022.9

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  • Lautropia mirabilisの分離・培養および検出法の確立と分離株の薬剤感受性に関する解析

    佐藤 あやめ, 中山 真彰, 藤井 伸治, 松岡 賢市, 前田 嘉信, 和田 崇之, 曽我 賢彦, 大原 直也

    日本細菌学雑誌   77 ( 1 )   61 - 61   2022.2

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  • Porphyromonas gingivalisジンジパインによるCOX-2発現とPGE2産生におけるカルシウムチャネルの役割

    中山 真彰, 内藤 真理子, 中山 浩次, 大原 直也

    日本細菌学雑誌   77 ( 1 )   86 - 86   2022.2

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  • 16S rRNA遺伝子の513シトシン挿入変異を有するストレプトマイシン依存性Mycobacterium bovis BCG株(Streptomycin dependent Mycobacterium bovis BCG possessing a 513 cytosine insertion in 16S rRNA gene)

    本田 尚子, 佐藤 法仁, 中山 真彰, 松村 隆之, 関塚 剛史, 黒田 誠, 阿戸 学, 小林 和夫, 石井 孝司, 大原 直也

    日本細菌学雑誌   77 ( 1 )   112 - 112   2022.2

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  • Analysis of cytotoxicity of intact Mycobacterium tuberculosis for human lung fibroblasts Reviewed

    77 ( 1 )   93 - 93   2022.2

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  • The role of phospholipase on Porphyromonas gingivalis gingipains-induced COX-2 expression and PGE2 production

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2022   2022

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  • カルシウムチャネルを介したPorphyromonas gingivalisジンジパインによるCOX-2発現の分子機序(The molecular mechanism of Porphyromonas gingivalis gingipains-induced COX-2 expression via the calcium channels)

    中山 真彰, 内藤 真理子, 中山 浩次, 大原 直也

    Journal of Oral Biosciences Supplement   2021   285 - 285   2021.10

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  • 結核ワクチンBCG Tokyo172 type Iとtype II間の酸化ストレス応答の違い Reviewed

    谷口 恵一, 林 大介, 小川 翔大, 宮竹 佑治, 安田 直美, 中山 真央, 伊藤 佐生智, 前山 順一, 大原 直也, 山本 三郎, 肥田 重明, 小野嵜 菊夫, 瀧井 猛将

    日本薬学会年会要旨集   141年会   27V10 - pm15   2021.3

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  • 四半世紀に及んだ腸管出血性大腸菌感染症の戦いと未来 感染症ミューズ細胞治療の挑戦(Quarter century battle against EHEC infectious disease; Muse cell therapy challenge on infectious diseases)

    藤井 潤, 出澤 真理, 尾鶴 亮, 若尾 昌平, 辻 高寛, 松葉 隆司, 黒沢 洋一, 大原 直也, 松本 壮吉, 安田 香央里, 飯野 守男

    日本細菌学雑誌   76 ( 1 )   126 - 126   2021.2

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  • 新たな視点から口腔内細菌を見つめる-個々の病原体から菌叢解析まで- P.gingivalisジンジパインによるCOX-2発現における細胞外カルシウム流入の重要性

    中山 真彰, 内藤 真理子, 中山 浩次, 大原 直也

    日本細菌学雑誌   76 ( 1 )   50 - 50   2021.2

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  • The significance of calcium influx on COX-2 expression induced by P. gingivalis gingipains

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌(Web)   76 ( 1 )   2021

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  • P.gingivalisジンジパインによるCOX-2発現と細胞外カルシウム流入の分子機序

    中山 真彰, 内藤 真理子, 中山 浩次, 大原 直也

    Journal of Oral Biosciences Supplement   2020   219 - 219   2020.9

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  • PCRをベースとしたLautropia mirabilisの簡便な検出法と分離法の検討

    佐藤 あやめ, 中山 真彰, 中川 美緒, 小崎 弘貴, 室 美里, 曽我 賢彦, 大原 直也

    日本細菌学雑誌   75 ( 1 )   66 - 66   2020.1

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  • 抗酸菌ヒストン様タンパク質の天然変性領域依存的なDNA凝集作用

    西山 晃史, 成田 知恕, 古寺 哲幸, 小林 瑶子, 武藤 寛亨, 渡辺 順也, 大原 直也, 尾関 百合子, 立石 善隆, 松本 壮吉

    日本細菌学雑誌   75 ( 1 )   132 - 132   2020.1

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  • 16S rRNA遺伝子の513シトシン挿入変異を有するストレプトマイシン依存性Mycobacterium bovis BCG株(Streptomycin dependent Mycobacterium bovis BCG possessing a 513 cytosine insertion in 16S rRNA gene)

    本田 尚子, 佐藤 法仁, 中山 真彰, 松村 隆之, 関塚 剛史, 黒田 誠, 阿戸 学, 小林 和夫, 石井 孝司, 大原 直也

    日本細菌学雑誌   75 ( 1 )   154 - 154   2020.1

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  • P.gingivalisジンジパイン誘導性COX-2発現における細胞外カルシウム流入の関与

    中山 真彰, 内藤 真理子, 中山 浩次, 大原 直也

    日本細菌学雑誌   75 ( 1 )   88 - 88   2020.1

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  • Comparison of differential gene expression in mycobacterial biofilm formation vs dormancy

    西内由紀子, 大田篤, 矢野大和, 岩本朋忠, 阿戸学, 松本壮吉, 大原直也, 丸山史人

    Bacterial Adherence & Biofilm   33   2020

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  • The involvement of calcium inflax on P. gingivalis gingipains-induced COX-2 expression

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌(Web)   75 ( 1 )   2020

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  • Development of a culture method and a PCR-based method for detection of Lautropia mirabilis.

    佐藤あやめ, 佐藤あやめ, 中山真彰, 中山真彰, 中川美緒, 小崎弘貴, 室美里, 曽我賢彦, 大原直也, 大原直也

    日本細菌学雑誌(Web)   75 ( 1 )   2020

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  • The molecular mechanism between COX-2 expression and calcium influx by P. gingivalis gingipains

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2020   2020

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  • The host cell death induced by the infection of intact Mycobacterium tuberculosis bacilli.

    中山真央, 谷口恵一, 長谷川倫弘, 田中崇宏, 櫻田紳策, 大原直也, 伊藤佐生智, 肥田重明, 小野嵜菊夫, 瀧井猛将, 瀧井猛将

    日本細菌学雑誌(Web)   75 ( 1 )   2020

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  • 結核菌感染ヒト肺線維芽細胞の細胞死の解析

    瀧井猛将, 瀧井猛将, 中山真央, 安田直美, 山田博之, 大原直也, 伊藤佐生智, 肥田重明, 小野嵜菊夫

    微生物シンポジウム講演要旨集   32nd (CD-ROM)   2020

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  • Analysis of host cell death induced by Mycobacterium tuberculosis bacilli-Role of inflammasome activation-

    中山真央, 安田直美, 谷口恵一, 長谷川倫宏, 大原直也, 伊藤佐生智, 肥田重明, 小野嵜菊夫, 瀧井猛将, 瀧井猛将

    日本薬学会年会要旨集(CD-ROM)   140th   2020

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  • Porphyromonas gingivalisのPGN_0297の機能解析

    小野 晋太郎, 中山 真彰, 大原 直也, 高柴 正悟

    日本歯周病学会会誌   61 ( 秋季特別 )   124 - 124   2019.10

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  • Porphyromonas gingivalis PGN_0296オペロンの解析

    小野 晋太郎, 中山 真彰, A Shahriar, 大原 直也

    Journal of Oral Biosciences Supplement   2019   291 - 291   2019.10

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  • Porphyromonas gingivalis gingipainsによるCOX2発現とPGE2産生における細胞内カルシウムの関与

    中山 真彰, 内藤 真理子, 中山 浩次, 大原 直也

    Journal of Oral Biosciences Supplement   2019   275 - 275   2019.10

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  • 非結核性抗酸菌におけるpYT系プラスミド利用の可能性

    野崎 高儀, 中山 真彰, 小川 みどり, 吉田 志緒美, 阿戸 学, 大原 直也

    日本細菌学雑誌   74 ( 1 )   88 - 88   2019.3

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  • 急速に増殖するMycobacterium aviumの亜種のhominissuis 104株の分析(Analysis of a rapid growing Mycobacterium avium subspecies hominissuis 104 strain)

    河喜多 智美, 吉田 光範, 鈴木 仁人, 中田 登, 瀧井 猛将, 中山 真彰, 梁 明秀, 星野 仁彦, 阿戸 学, 大原 直也

    日本細菌学雑誌   74 ( 1 )   61 - 61   2019.3

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  • マイコファージによる非結核性抗酸菌症の予防法と治療法の確立

    島守 祐月, 大原 直也, 露口 一成, 大屋 賢司, 吉田 志緒美, 武田 茂樹, 永井 宏樹, 安藤 弘樹

    日本細菌学雑誌   74 ( 1 )   51 - 51   2019.3

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  • マイコファージによる非結核性抗酸菌症の予防法と治療法の確立

    島守 祐月, 大原 直也, 露口 一成, 大屋 賢司, 吉田 志緒美, 武田 茂樹, 永井 宏樹, 安藤 弘樹

    日本細菌学雑誌   74 ( 1 )   51 - 51   2019.3

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  • 非結核性抗酸菌におけるpYT系プラスミド利用の可能性

    野崎 高儀, 中山 真彰, 小川 みどり, 吉田 志緒美, 阿戸 学, 大原 直也

    日本細菌学雑誌   74 ( 1 )   88 - 88   2019.3

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  • pYTプラスミドの非結核性抗酸菌における応用の可能性の検討

    野崎 高儀, 中山 真彰, 小川 みどり, 吉田 志緒美, 阿戸 学, 大原 直也

    結核   94 ( 3 )   293 - 293   2019.3

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  • 非結核性抗酸菌のバイオフィルム形成条件における遺伝子発現解析(Detection of Differential Gene Expression in Biofilm-Forming Mycobacterium avium subsp. hominissuis)

    西内 由紀子, 大田 篤, 岩本 朋忠, 阿戸 学, 松本 壮吉, 大原 直也, 丸山 史人

    日本細菌学雑誌   74 ( 1 )   109 - 109   2019.3

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  • トリ型結核菌Mycobacterium aviumの酸性環境下における適応機構の解析

    瀧井 猛将, 小川 翔大, 大原 直也, 小川 賢二, 八木 哲也, 藤原 永年, 前田 伸司, 伊藤 佐生智, 肥田 重明, 小野崎 菊夫

    日本細菌学雑誌   74 ( 1 )   55 - 55   2019.3

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  • 菌の休眠と覚醒のメカニズムと意義 休眠中のマイコバクテリアの主要タンパク質であるマイコバクテリアのヒストン様タンパク質MDP1の機能(The functions of mycobacterial histone-like protein MDP1, a major protein in dormant mycobacteria)

    西山 晃史, Savitskaya Anna, 山口 雄大, 大原 直也, 成田 知恕, 古寺 哲幸, 尾関 百合子, 立石 善隆, 松本 壮吉

    日本細菌学雑誌   74 ( 1 )   8 - 8   2019.3

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  • Porphyromonas gingivalis PGN_0296オペロンの解析

    小野晋太郎, 中山真彰, SHAHRIAR A, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2019   2019

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  • マイコバクテリア病原因子Zmp1の自然免疫およびT細胞免疫応答への影響

    梅村正幸, 梅村正幸, 木村倫和, 岩橋晃平, 藏根友美, 照屋尚子, 中山真彰, 大原直也, 高江洲義一, 高江洲義一, 松崎吾朗, 松崎吾朗

    日本熱帯医学会大会プログラム抄録集   60th   2019

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  • 病原因子Zmp1欠損マイコバクテリアによるT細胞免疫応答への影響

    梅村正幸, 梅村正幸, 梅村正幸, 藏根友美, 中山真彰, 大原直也, 高江洲義一, 高江洲義一, 高江洲義一, 松崎吾朗, 松崎吾朗, 松崎吾朗

    日本インターフェロン・サイトカイン学会学術集会抄録集   84th   2019

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  • Porphyromonas gingivalisのPGN_0297の機能解析

    小野晋太郎, 中山真彰, 大原直也, 高柴正悟

    日本歯周病学会会誌(Web)   61   2019

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  • The role of Ca2+ on Porphyromonas gingivalis gingipains-induced COX-2 expression

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌(Web)   74 ( 1 )   2019

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  • Porphyromonas gingivalis gingipainsによるCOX2発現とPGE2産生における細胞内カルシウムの関与

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2019   2019

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  • 結核菌によるヒト肺線維芽細胞の細胞死の解析

    中山真央, 安田直美, 谷口恵一, 長谷川倫宏, 田中崇裕, 櫻田紳策, 大原直也, 伊藤佐生智, 肥田重明, 小野嵜菊夫, 瀧井猛将, 瀧井猛将

    微生物シンポジウム講演要旨集   31st   2019

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  • 健常者口腔内からのLautropia mirabilisの分離とL.mirabilis検出方法の確立

    佐藤あやめ, 佐藤あやめ, 中山真彰, 中山真彰, 中川美緒, 小崎弘貴, 室美里, 曽我賢彦, 大原直也, 大原直也

    岡山歯学会雑誌   38 ( 2 )   2019

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  • Analysis of the adaptation mechanism of Mycobacterium avium under the acid environment

    瀧井猛将, 瀧井猛将, 小川翔大, 大原直也, 小川賢二, 八木哲也, 藤原永年, 前田伸司, 伊藤佐生智, 肥田重明, 小野嵜菊夫

    日本細菌学雑誌(Web)   74 ( 1 )   2019

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  • The possibility of the pYT plasmid in the use of genetic analysis of NTM

    野崎高儀, 野崎高儀, 中山真彰, 小川みどり, 吉田志緒美, 阿戸学, 大原直也

    日本細菌学雑誌(Web)   74 ( 1 )   2019

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  • Porphyromonas gingivalisのジンジパインの機能発現におけるPGN_0297の役割

    小野 晋太郎, 高柴 正悟, 大原 直也

    岡山歯学会雑誌   37 ( 2 )   81 - 82   2018.12

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  • チミジル酸合成酵素遺伝子過剰発現によるBCGの増殖速度の促進とその機序の解明

    大原直也, 大原直也, 和田崇之, 阿戸学, 鈴木定彦

    結核   93 ( 4 )   290   2018.4

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  • マウスにおいてIL-21はBCG感染後に短命のエフェクターCD8+T細胞を誘導する(IL-21 induces short-lived effector CD8+ T cells after BCG infection in mice) Reviewed

    野口 直人, 中村 梨沙, 畑野 晋也, 山田 久方, Sun Xun, 大原 直也, 吉開 泰信

    日本細菌学雑誌   73 ( 1 )   132 - 132   2018.2

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  • BCGの増殖率促進に関与する遺伝子の調査(Investigation of genes involved in promoting the growth rate of BCG)

    竜門 亜矢子, 中山 真彰, 和田 崇之, 橘 理人, 阿戸 学, 中島 千絵, 鈴木 定彦, 小崎 弘貴, 大原 直也

    日本細菌学雑誌   73 ( 1 )   68 - 68   2018.2

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  • Investigation of genes involved in promoting the growth rate of BCG

    竜門亜矢子, 中山真彰, 中山真彰, 和田崇之, 橘理人, 阿戸学, 中島千絵, 鈴木定彦, 小崎弘貴, 大原直也, 大原直也

    日本細菌学雑誌(Web)   73 ( 1 )   2018

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  • Porphyromonas gingivalis gingipainsによるMEK/ERK/AP-1およびIKK/NF-kBp65の活性化を介したCOX-2発現およびPGE2産生の誘導機構

    中山真彰, 中山真彰, 内藤真理子, 橘理人, 中山浩次, 大原直也, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2018   2018

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  • Porphyromonas gingivalisジンジパインによるCOX-2発現誘導を介したPGE2産生の分子解析

    中山真彰, 中山真彰, 内藤真理子, 橘理人, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌(Web)   73 ( 1 )   2018

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  • BCG Rv3405cによるRv3406の遺伝子発現抑制機構の解析

    白崎かおり, 白崎かおり, 中山真彰, 橘理人, 山本三郎, 瀧井猛将, 岡部真裕子, 阿戸学, 上岡寛, 大原直也

    日本細菌学雑誌(Web)   73 ( 1 )   2018

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  • 歯学教育認証評価検討WGによる歯学教育認証評価トライアルを受審して

    川瀬 明子, 宮脇 卓也, 久保田 聡, 松尾 龍二, 大原 直也, 松本 卓也, 鳥井 康弘, 飯田 征二, 窪木 拓男, 浅海 淳一, 岡山大学歯学部歯学教育認証評価トライアル対策WG

    日本歯科医学教育学会総会・学術大会プログラム・抄録集   36回   110 - 110   2017.7

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  • 抗酸菌における誘導発現系を用いたmycobacterial DNA-binding protein 1の機能解析(Conditional expression of mycobacterial DNA-binding protein 1 function in mycobacteria)

    Savitskaya Anna G, 西山 晃史, 大原 直也, 松本 壮吉

    日本細菌学雑誌   72 ( 1 )   97 - 97   2017.2

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  • Porphyromonas gingivalisジンジパインによるCOX-2発現とPGE2産生の分子機序

    中山真彰, 中山真彰, 橘理人, 橘理人, 内藤真理子, 中山浩次, 大原直也, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2017   2017

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  • PDIM/PGLはBCGの胆汁酸に対する抵抗性に関与する

    田村庄平, 中山真彰, 藤原永年, 和田崇之, 山本三郎, 小崎弘貴, 飯田征二, 大原直也

    日本細菌学雑誌(Web)   72 ( 1 )   2017

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  • Porphyromonas gingivalisジンジパインによるPGE2産生の分子機序

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌(Web)   72 ( 1 )   2017

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  • BCG ThyA,ThyX変異株の解析

    竜門亜矢子, 中山真彰, 橘理人, 小崎弘貴, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2017   2017

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  • 非結核性抗酸菌(non-tuberculous mycobacteria,NTM)の薬剤排出能に関する検討

    小崎弘貴, 中山真彰, 橘理人, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2017   2017

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  • BCG Tokyo RD16領域に存在するJTY_3475cはJTY_3476の遺伝子発現を負に制御する

    白崎かおり, 中山真彰, 山本三郎, 瀧井猛将, 岡部真裕子, 阿戸学, 上岡寛, 大原直也

    日本細菌学雑誌(Web)   72 ( 1 )   2017

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  • 歯周病におけるP.gingivalisジンジパインの重要性

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌(Web)   72 ( 1 )   2017

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  • BCG thyXを用いた抗酸菌のPAS耐性機序の解析

    大原直也, 大原直也, 阿戸学, 鈴木定彦, 小林和夫

    結核   91 ( 3 )   325 - 325   2016.3

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  • 次世代シーケンサーを用いたBCG Tokyo 172のシードロットおよび市販ロットにおけるヘテロ変異検出

    和田 崇之, 岩本 朋忠, 前田 伸司, 山本 太郎, 山本 三郎, 大原 直也, 中川 一路, 丸山 史人

    結核   91 ( 3 )   326 - 326   2016.3

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  • 抗酸菌のPAS耐性機序の解明 BCG thyX欠損株および過剰発現株の作製

    有村 友紀, 中山 真彰, 妹尾 昌紀, 田川 淳平, 阿戸 学, 中島 千絵, 鈴木 定彦, 中山 浩次, 小林 和夫, 大原 直也

    日本細菌学雑誌   71 ( 1 )   142 - 142   2016.2

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  • 次世代シーケンサーによるBCGワクチンのシードロットと市販ロットにおけるヘテロ変異の検出

    和田 崇之, 丸山 史人, 岩本 朋忠, 山本 太郎, 中川 一路, 山本 三郎, 大原 直也

    日本細菌学雑誌   71 ( 1 )   134 - 134   2016.2

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  • Porphyromonas gingivalis ECFシグマ因子変異株における菌体表層性状の解析

    菊池有一郎, 菊池有一郎, 国分栄仁, 国分栄仁, 柴山和子, 大原直也, 中山浩次, 石原和幸, 石原和幸

    Journal of Oral Biosciences Supplement (Web)   2016   2016

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  • PI3K/Akt経路に対するP.gingivalisジンジパインの役割

    中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2016   2016

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  • BCGにおけるcyclic-di-GMP菌体内合成の影響

    妹尾 昌紀, 中山 真彰, 有村 友紀, 飯田 征二, 大原 直也

    Journal of Oral Biosciences Supplement   2015   331 - 331   2015.9

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  • BCG thyX欠損株の作製とその性状解析

    有村 友紀, 中山 真彰, 妹尾 昌紀, 田川 淳平, 中山 浩次, 飯田 征二, 大原 直也

    Journal of Oral Biosciences Supplement   2015   330 - 330   2015.9

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  • The deletion of glycopeptidolipid in Mycobacterium smegmatis J15cs strain affects morphology and survival in host cells

    N. Fujiwara, M. Ayata, N. Ohara, M. Ogawa, T. Naka, H. Taniguchi, S. Yamamoto, S. Maeda

    FEBS JOURNAL   282   238 - 238   2015.7

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  • 抗酸菌におけるパラアミノサリチル酸に対する新たな耐性機序の可能性

    ZHAO NA, NAKAYAMA MASAAKI, SEKIZUKA TSUYOSHI, KURODA MAKOTO, HONDA NAOKO, ATO MANABU, NAKAJIMA CHIE, SUZUKI YASUHIKO, OHARA NAOYA

    日本細菌学雑誌   70 ( 1 )   193   2015.2

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  • 結核に対する新規ワクチンIL-7産生BCGの開発(Development of a recombinant BCG expressing murine IL-7 as a novel vaccine against tuberculosis)

    畑野 晋也, 柴田 健輔, 山田 久方, 大原 直也, 田村 敏生, 吉開 泰信

    日本細菌学雑誌   70 ( 1 )   235 - 235   2015.2

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  • 結核菌の潜伏、持続感染の分子遺伝学

    大原直也

    化学療法の領域   31 ( 9 )   101 - 106   2015

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  • Porphyromonas gingivalis ECFシグマ因子変異株の性状解析

    菊池有一郎, 柴山和子, 国分栄仁, 国分栄仁, 大原直也, 中山浩次, 石原和幸, 石原和幸

    Journal of Oral Biosciences Supplement (Web)   2015   2015

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  • BCGにおけるcyclic-di-GMP菌体内合成の影響

    妹尾昌紀, 中山真彰, 有村友紀, 飯田征二, 大原直也, 飯田征二, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2015   2015

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  • BCG thyX欠損株の作製とその性状解析

    有村友紀, 中山真彰, 妹尾昌紀, 田川淳平, 中山浩次, 飯田征二, 大原直也, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2015   2015

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  • 細菌感染による破骨細胞分化への自然免疫応答の重要性

    中山真彰, 中山真彰, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌   70 ( 1 )   2015

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  • 歯周病原細菌の感染による免疫応答と破骨細胞分化制御の相関性

    中山真彰, 中山真彰, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌   70 ( 1 )   2015

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  • Porphyromonas gingivalis ATCC 33277株rpoN低発現株の性状解析

    加野小奈美, 井上哲圭, 田口裕子, 田川淳平, 中山真彰, 内藤真理子, 中山浩次, 大原直也

    日本細菌学雑誌   70 ( 1 )   2015

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  • P.gingivalisジンジパインによるPI3K/Akt経路の抑制効果とその意義

    中山真彰, 内藤真理子, 中山浩次, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2015   2015

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  • Porphyromonas gingivalisの表層蛋白質の修飾と機能に関与する分子の解析

    田口裕子, 佐藤啓子, 雪竹英治, 井上哲圭, 井上哲圭, 中山真彰, 中山真彰, 内藤真理子, 中山浩次, 大原直也, 大原直也

    日本細菌学雑誌   70 ( 1 )   2015

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  • 岡山大学医学部1年次生に対する歯学部早期体験実習の試み

    縄稚 久美子, 吉田 登志子, 曽我 賢彦, 村田 尚道, 仲野 道代, 大原 直也, 鳥井 康弘, 窪木 拓男

    日本歯科医学教育学会総会・学術大会プログラム・抄録集   33回   151 - 151   2014.7

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  • 双方向的岡山大学国際交流演習(ODAPUSプログラム)に参加して

    菅藤 綾乃, 王 碩, 実藤 和典, 松田 明莉, 大原 直也, 宮脇 卓也, 浅海 淳一, 窪木 拓男

    日本歯科医学教育学会総会・学術大会プログラム・抄録集   33回   159 - 159   2014.7

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  • バイオフィルム形成におけるPorphyromonas gingivalisECFシグマ因子の役割

    菊池有一郎, 菊池有一郎, 柴山和子, 国分栄仁, 国分栄仁, 大原直也, 中山浩次, 石原和幸, 石原和幸

    Journal of Oral Biosciences Supplement (Web)   2014   2014

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  • 口腔癌細胞株担癌マウスに対するBCG生菌と5-FU併用療法による延命効果の検討

    村上純, 大原直也, 中山真彰, 辻極秀次, 長塚仁, 此内浩信, 柳文修, 苔口進, 久富美紀, 藤田麻里子, 畦坪輝寿, 浅海淳一

    日本癌治療学会学術集会(CD-ROM)   52nd   2014

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  • Porphyromonas gingivalisではsigma-54をコードするPGN_1202(rpoN)は必須遺伝子である

    加野小奈美, 井上哲圭, 田口裕子, 中山真彰, 内藤真理子, 中山浩次, 大原直也

    日本細菌学雑誌   69 ( 1 )   2014

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  • Porphyromonas gingivalisにおける菌体外のジンジパインの酵素活性に関わる新規遺伝子について

    田口裕子, 井上哲圭, 佐藤啓子, 加野小奈美, 中山真彰, 内藤真理子, 中山浩次, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2014   2014

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  • 細菌感染による免疫応答が破骨細胞分化に与える影響

    中山真彰, 井上哲圭, 中山浩次, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2014   2014

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  • Porphyromonas gingivalisの薬剤排出ポンプ欠損株の薬剤感受性と細胞内侵入性

    井上哲圭, 井上哲圭, 田口裕子, 加野小奈美, 中山真彰, 黒田照夫, 大原直也, 大原直也

    日本細菌学雑誌   69 ( 1 )   2014

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  • Porphyromonas gingivalis PGN1796変異株の細胞内侵入性および薬剤感受性

    田口裕子, 井上哲圭, 佐藤啓子, 加野小奈美, 中山真彰, 中山浩次, 大原直也

    日本細菌学雑誌   69 ( 1 )   2014

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  • 異所性感染および全身疾患に対する歯周病原細菌の病原性の理解

    中山真彰, 大原直也

    日本臨床腸内微生物学会誌   16 ( 1 )   2014

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  • P.gingivalisジンジパインのタンパク分解作用によるPI3K/Akt経路への影響

    中山真彰, 井上哲圭, 中山浩次, 大原直也

    日本細菌学雑誌   69 ( 1 )   2014

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  • BCG Tokyo-172 Type I,Type II間の酸化ストレス感受性とマクロファージ内生存能の比較研究

    瀧井猛将, 宮竹佑治, 小川翔大, 谷口恵一, 伊藤佐生智, 大原直也, 前山順一, 林大介, 山本三郎

    日本細菌学雑誌   69 ( 1 )   2014

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  • BCG Tokyo172Type I,Type II間の酸化ストレス感受性とマクロファージ内生存能及びサイトカイン誘導能の比較研究

    瀧井猛将, 伊藤佐生智, 大原直也, 前山順一, 林大介, 山本三郎

    結核   89 ( 3 )   2014

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  • Mycobacterium aviumにおける酸性環境下でのアルギニンデイミナーゼの発現誘導機構の解析

    小川翔大, 小川賢二, 八木哲也, 大原直也, 後藤義孝, 藤原永年, 前田伸司, 伊藤佐生智, 筑比地慧, 宮田江里香, 高見篤郎, 徳田美季, 富田陽香, 小野嵜菊夫, 瀧井猛将

    日本薬学会年会要旨集(CD-ROM)   134th   2014

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  • 菌体内pHの低下によるMycobacterim aviumのarcA mRNAの発現変化の解析

    小川翔大, 小川賢二, 八木哲也, 大原直也, 後藤義孝, 藤原永年, 前田伸司, 山崎利雄, 伊藤佐生智, 瀧井猛将

    日本細菌学雑誌   69 ( 1 )   2014

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  • 電気穿孔法に適したPorphyromonas gingivalis用新規プラスミドベクターの構築

    田川 淳平, 井上 哲圭, 大原 直也, 山城 隆

    日本矯正歯科学会大会プログラム・抄録集   72回   210 - 210   2013.10

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  • Porphyromonas gingivalis PGN_1796は薬剤感受性に関与する

    田口 裕子, 井上 哲圭, 大原 直也, 前田 博史, 高柴 正悟

    特定非営利活動法人日本歯科保存学会学術大会プログラムおよび講演抄録集   139回   95 - 95   2013.10

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  • Porphyromonas gingivalisにおいて電気穿孔法で導入可能なプラスミドベクターの構築

    田川 淳平, 井上 哲圭, 佐藤 啓子, 内藤 真理子, 中山 真彰, 中山 浩次, 山城 隆, 大原 直也

    Journal of Oral Biosciences Supplement   2013   113 - 113   2013.9

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  • 口腔癌に対するBCG生菌療法による抗腫瘍、延命効果の検討

    村上 純, 大原 直也, 中山 真彰, 辻極 秀次, 長塚 仁, 此内 浩信, 柳 文修, 畦坪 輝寿, 浅海 淳一

    Journal of Oral Biosciences Supplement   2013   222 - 222   2013.9

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  • Porphyromonas gingivalisのPGN_1202(rpoN)は必須遺伝子である

    加野 小奈美, 井上 哲圭, 田口 裕子, 田川 淳平, 中山 真彰, 山城 隆, 大原 直也

    Journal of Oral Biosciences Supplement   2013   169 - 169   2013.9

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  • Porphyromonas gingivalisにおいて電気穿孔法で導入可能なプラスミドベクターの構築

    田川 淳平, 井上 哲圭, 佐藤 啓子, 内藤 真理子, 中山 真彰, 中山 浩次, 山城 隆, 大原 直也

    Journal of Oral Biosciences Supplement   2013   167 - 167   2013.9

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  • New insights into the virulence factors of Mycobacterium tuberculosis

    246 ( 6 )   465 - 469   2013.8

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  • バイオフィルム形成におけるPorphyromonas gingivalis ECFシグマ因子の役割

    菊池有一郎, 菊池有一郎, 柴山和子, 国分栄仁, 国分栄仁, 大原直也, 中山浩次, 石原和幸

    Journal of Oral Biosciences Supplement (Web)   2013   2013

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  • Porphyromonas gingivalisの薬剤排出ポンプ様分子をコードする遺伝子

    井上哲圭, 田口裕子, 加野小奈美, 中山真彰, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2013   2013

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  • P.gingivalisジンジパインによるPI3K/Akt経路の抑制機序

    中山真彰, 井上哲圭, 中山浩次, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2013   2013

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  • P.gingivalisジンジパインによるPI3K/Akt経路の抑制機序

    中山真彰, 井上哲圭, 内藤真理子, 中山浩次, 大原直也

    日本細菌学雑誌   68 ( 1 )   2013

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  • Porphyromonas gingivalisにおける薬剤排出ポンプ様遺伝子破壊株の薬剤感受性

    井上哲圭, 中山真彰, 大原直也

    日本細菌学雑誌   68 ( 1 )   2013

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  • 口腔癌に対するBCG生菌療法による抗腫瘍,延命効果の検討

    村上純, 大原直也, 中山真彰, 辻極秀次, 長塚仁, 此内浩信, 柳文修, 畦坪輝寿, 浅海淳一

    Journal of Oral Biosciences Supplement (Web)   2013   2013

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  • Porphyromonas gingivalisのPGN_1202(rpoN)は必須遺伝子である

    加野小奈美, 井上哲圭, 田口裕子, 田川淳平, 中山真彰, 山城隆, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2013   2013

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  • Porphyromonas gingivalisにおいて電気穿孔法で導入可能なプラスミドベクターの構築

    田川淳平, 井上哲圭, 佐藤啓子, 内藤真理子, 中山真彰, 中山浩次, 山城隆, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2013   2013

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  • 国際共同基盤研究に応用する抗酸菌感染症研究の整備 宿主への侵入および宿主内生存に関わる抗酸菌の分子と宿主要因に関する研究

    大原直也, 小林和夫, 中山真彰, 井上哲圭

    国際共同基盤研究に応用する抗酸菌感染症研究の整備 平成24年度 総括・分担研究報告書   2013

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  • トリ型結核菌Mycobacterium aviumのアミノ酸代謝とアンモニア産生に関する研究

    花村菜月, 堀田康弘, 伊藤佐生智, 小川賢二, 八木哲也, 西森敬, 大原直也, 藤原永年, 前田伸司, 山崎利雄, 瀧井猛将

    結核   88 ( 2 )   2013

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  • [Mycobacterium tuberculosis]. Reviewed

    Ohara N

    Nihon rinsho. Japanese journal of clinical medicine   70 ( 2 )   243 - 246   2012.2

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  • 歯肉上皮細胞におけるPorphyromonas gingivalis HbRによるIL-8産生

    藤田佑貴, 藤田佑貴, 中山真彰, 内藤真理子, 山近英樹, 中山浩次, 大原直也, 飯田征二

    日本細菌学雑誌   67 ( 1 )   2012

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  • Porphyromonas gingivalisによるAkt脱リン酸化機構とその意義

    中山真彰, 藤田佑貴, 井上哲圭, 大原直也

    日本細菌学雑誌   67 ( 1 )   2012

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  • Porphyromonas gingivalis由来タンパク質HbRのIL-8産生誘導解析

    中山真彰, 藤田佑貴, 藤田佑貴, 内藤真理子, 中山浩次, 大原直也

    トキシンシンポジウム予稿集   59th   2012

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  • Porphyromonas gingivalisによるAkt/GSK3betapathwayの制御

    中山真彰, 井上哲圭, 大原直也

    Journal of Oral Biosciences Supplement (Web)   2012   2012

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  • 非結核性抗酸菌Mycobacterium aviumのpH環境変化におけるarcA遺伝子発現の解析

    小川翔大, 瀧井猛将, 伊藤佐生智, 山本龍二, 堀田康弘, 堀田康弘, 花村菜月, 宮田江里香, 小川賢二, 八木哲也, 大原直也, 後藤義孝, 後藤義孝, 藤原永年, 前田伸司, 西森敬, 山崎利雄, 小野嵜菊夫

    微生物シンポジウム講演要旨集   24th   2012

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  • トリ型結核菌Mycobacterium aviumの増殖とアンモニア産生に関する研究

    花村菜月, 瀧井猛将, 宮田江里香, 筑比地慧, 伊藤佐生智, 山本龍二, 堀田康弘, 小川賢二, 八木哲也, 西森敬, 大原直也, 藤原永年, 前田伸司, 山崎利雄, 後藤義孝, 小野嵜菊夫

    衛生薬学・環境トキシコロジー講演要旨集   2012   2012

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  • Mycobcterium avium subsp.hominissuis特異的菌体外pH上昇に関する研究

    小川翔大, 瀧井猛将, 山本龍二, 堀田康弘, 堀田康弘, 花村菜月, 宮田江里香, 小川賢二, 八木哲也, 西森敬, 大原直也, 後藤義孝, 藤原永年, 前田伸司, 伊藤佐生智, 小野嵜菊夫

    日本薬学会年会要旨集   132nd ( 3 )   2012

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  • Mycobacterium avium亜種(avium・hominissuis)間での酸性環境下における菌体外pH上昇に関与するアンモニア産生経路の研究

    花村菜月, 堀田康弘, 小川賢二, 八木哲也, 西森敬, 大原直也, 藤原永年, 前田伸司, 山崎利雄, 伊藤佐生智, 瀧井猛将

    結核   87 ( 3 )   2012

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  • 国際共同基盤研究に応用する抗酸菌感染症研究の整備 結核菌の分子遺伝学

    谷口初美, 藤原永年, 大原直也, 福田和正, 小川みどり

    国際共同基盤研究に応用する抗酸菌感染症研究の整備 平成22年度 総括・分担研究報告書   35 - 38   2011

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  • トリ型結核菌亜種hominissuisのアンモニア産生と宿主細胞内生存能との関連性

    伊藤佐生智, 山本龍二, 堀田康弘, 小川賢二, 八木哲也, 大原直也, 瀧井猛将

    結核   86 ( 3 )   2011

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  • 国際共同基盤研究に応用する抗酸菌感染症研究の整備 宿主への侵入および宿主内生存に関わる抗酸菌の分子と宿主要因に関する研究

    大原直也, 小林和夫, 岡部真裕子, 中山真彰

    国際共同基盤研究に応用する抗酸菌感染症研究の整備 平成22年度 総括・分担研究報告書   2011

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  • Mycobacterium smegmatis J15csの結核菌細胞内増殖の分子遺伝学的研究への応用(2):rpoZ mutantの解析

    小川みどり, 大原直也, 野本摩利, 福田和正, 谷口初美

    日本細菌学雑誌   65 ( 1 )   2010

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  • 抗酸菌感染症の発症・診断・治療・新世代予防技術に係わる分子機構に関する研究 結核菌潜伏感染の分子機構と治療・予防戦略

    小林和夫, 前倉亮治, 北田清悟, 松本壮吉, 藤原永年, 阿戸学, 大西和夫, 高橋宜聖, 岡部真裕子, 大原直也

    抗酸菌感染症の発症・診断・治療・新世代予防技術に係わる分子機構に関する研究 平成21年度 総括・分担研究報告書   17 - 21   2010

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  • Porphyromonas gingivalis ECFシグマ因子PG0162変異株の性状解析 Reviewed

    菊池 有一郎, 大原 直也, 上田 青海, 平井 要, 柴田 幸永, 雪竹 英治, 中山 浩次, 藤村 節夫

    日本細菌学雑誌   64 ( 1 )   162 - 162   2009.2

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  • 持続性結核菌感染の病原性や発症に関わる分子機構の解明及び治療・予防の基礎研究 休眠抗酸菌と宿主応答

    小林和夫, 藤原永年, 大原直也, 阿戸学, 大西和夫, 高橋宜聖, 岡部真裕子

    持続性結核菌感染の病原性や発症に関わる分子機構の解明及び治療・予防の基礎研究 平成20年度 総括・分担研究報告書   11 - 14   2009

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  • 抗酸菌感染症の発症・診断・治療・新世代予防技術に係わる分子機構に関する研究 結核菌潜伏感染の分子機構と治療・予防戦略

    小林和夫, 前倉亮治, 北田清悟, 松本壮吉, 藤原永年, 大原直也, 阿戸学, 大西和夫, 高橋宜聖, 岡部真裕子

    抗酸菌感染症の発症・診断・治療・新世代予防技術に係わる分子機構に関する研究 平成20年度 総括・分担研究報告書   15 - 19   2009

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  • 結核菌による臓器侵襲の分子機構

    大原直也

    平成２０年度社会保障国際協力推進研究事業（国際医学研究事業）日米医学協力研究計画結核・ハンセン病専門部会年次報告書 (研究代表者 結核研究所 菅原勇)   2009

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  • 日本株BCG Tokyo 172-1 Ⅰ型とⅡ型の遺伝学的検討と新規BCG宿主ベクター系の作製

    大原直也

    平成２０年度政策創薬総合研究事業 細菌性ベクター及び粘膜アジュバントを用いた新興・再興感染症に対する新規予防・治療法の開発研究報告書（研究代表者 国立感染症研究所前山順一）   2009

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  • 抗酸菌（マイコバクテリア）感染症

    大原直也, 小林和夫

    コンパクト内科学   418 - 420   2009

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  • Porphyromonas gingivalis ECFシグマ因子PG0162変異株の性状解析 Reviewed

    菊池 有一郎, 大原 直也, 上田 青海, 平井 要, 柴田 幸永, 中山 浩次, 藤村 節夫

    Journal of Oral Biosciences   50 ( Suppl. )   212 - 212   2008.9

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  • 結核菌による臓器侵襲の分子機構

    大原直也

    平成１９年度社会保障国際協力推進研究事業日米医学協力研究計画結核・ハンセン病専門部会年次報告書 (研究代表者 結核研究所 菅原勇)   2008

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  • 新規結核ワクチンとしてのリコンビナントBCGに関する研究

    大原直也

    平成１９年度新興・再興感染症研究事業（アジア地域との研究ネットワークの活用による多剤耐性結核の制御に関する研究）研究報告書 (研究代表者 近畿中央胸部疾患センター 岡田全司)   2008

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  • 組換えBCGワクチンの改良・開発の研究

    大原直也

    新興・再興感染症研究事業（アジア地域との研究ネットワークの活用による多剤耐性結核の制御に関する研究）平成１７年度～１９年度総合研究報告書 (研究代表者 近畿中央胸部疾患センター 岡田全司)   2008

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  • 新規結核ワクチンとしてのリコンビナントBCGに関する研究

    大原直也

    平成１９年度新興・再興感染症研究事業（有用な結核対策（BCG及び結核感染特異的診断に関する費用対効果分析等）に関する研究）研究報告書 (研究代表者 近畿中央胸部疾患センター 坂谷光則)   2008

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  • 結核菌

    大原直也, 小林和夫

    バイオセーフティの事典―病原微生物とバイオハザード対策の実際―   194 - 197   2008

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  • 組換えBCGワクチンの改良・開発の研究

    大原直也

    新興・再興感染症研究事業（有用な結核対策（BCG及び結核感染特異的診断に関する費用対効果分析等）に関する研究）平成１７年度～１９年度総合研究報告書 (研究代表者 近畿中央胸部疾患センター 坂谷光則)   2008

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  • 多価ワクチンとしての活用を目指したBCG宿主－ベクター系の改良

    大原直也

    平成１９年度政策創薬総合研究事業 細菌性ベクター及び粘膜アジュバントを用いた新興・再興感染症に対する新規予防・治療法の開発研究報告書（研究代表者 国立感染症研究所前山順一）   2008

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  • ハンセン病

    大原直也

    微生物の事典   470 - 471   2008

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  • 結核 (特集 新興・再興感染症の現状と予防)

    岡部 真裕子, 大原 直也, 小林 和夫

    保健の科学   49 ( 10 )   691 - 697   2007.10

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    Other Link： http://search.jamas.or.jp/link/ui/2008041068

  • 細菌による破骨細胞分化の制御

    大原 直也

    日本細菌学雑誌   62 ( 1 )   65 - 65   2007.2

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  • Porphyromonas gingivalis ATCC33277 株の全ゲノム塩基配列決定

    内藤 真理子, 大原 直也, 庄子 幹郎, 中山 恵介, 吉村 文信, 林 哲也, 中山 浩次

    日本細菌学雑誌   62 ( 1 )   71 - 71   2007.2

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  • Porphyromonas gingivalis のTPRドメイン蛋白質欠損株の解析

    近藤 好夫, 吉村 満美子, 大原 直也, 庄子 幹郎, 雪竹 英治, 内藤 真理子, 藤原 卓, 中山 浩次

    日本細菌学雑誌   62 ( 1 )   115 - 115   2007.2

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  • 結核

    岡部真裕子, 大原直也, 小林和夫

    保健の科学   49 ( 10 )   691 - 697   2007

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  • TNF-α, lipopolysaccharide, and peptidoglycan induce cell fusion independently of RANKL at the latest step of differentiation of RAW264.7 cells into osteoclast-like cells. Reviewed

    Hotokezaka H, Sakai E, Ohara N, Hotokezaka Y, Gonzales C, Matsuo, K, Fujimura Y, Yoshida N, Nakayama K

    J Cell Biochem.   277 ( 21 )   18545 - 18551   2007

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  • TNF-alpha, lipopolysaccharide, and peptidoglycan induce cell fusion independently of RANKL at the latest step of differentiation of RAW264.7 cells into osteoclast-like cells

    Hotokezaka H, Sakai E, Ohara N, Hotokezaka Y, Gonzales C, Matsuo K, Fujimura Y, Yoshida N, Nakayama K

    Journal of Cellular Biochemistry   101 ( 1 )   122 - 134   2007

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  • 新規結核ワクチンとしてのリコンビナントBCGに関する研究

    大原直也

    平成１８年度新興・再興感染症研究事業（有用な結核対策（BCG及び結核感染特異的診断に関する費用対効果分析等）に関する研究）研究報告書 (研究代表者 近畿中央胸部疾患センター 坂谷光則)   2007

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  • 新規結核ワクチンとしてのリコンビナントBCGに関する研究

    大原直也

    平成１８年度新興・再興感染症研究事業（アジア地域との研究ネットワークの活用による多剤耐性結核の制御に関する研究）研究報告書 (研究代表者 近畿中央胸部疾患センター 岡田全司)   2007

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  • 結核菌による臓器侵襲の分子機構

    大原直也

    平成１8年度国際医学研究協力事業日米医学協力研究計画結核・ハンセン病専門部会年次報告書 (研究代表者 結核研究所 菅原勇)   2007

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  • A TLR4 gene polymorphism is associated with moderate and severe periodontitis in the Japanese population

    Fukusaki Tsuyoshi, Yoshimura Atsutoshi, Ohara Naoya, Muraoka Yuki, Yoshiura koh-ichiro, Hara Yoshitaka

    Program and Abstracts of Annual Meeting of the Japanese Society of Periodontology   2006 ( 0 )   48 - 48   2006

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  • PLC阻害剤はアムホテリシンBによるTLR2依存性NF-κB活性化を抑制する

    松尾 謙一郎, 佛坂 斉祉, 岡田 幸雄, 坂井 詠子, 内藤 真理子, 大原 直也, 吉田 教明, 中山 浩次

    Journal of oral biosciences   46 ( 5 )   489 - 489   2004.9

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  • Porphyromonas gingivalis感染による末梢血単球の分化への影響

    吉村 満美子, 大原 直也, 中山 浩次

    Journal of oral biosciences   46 ( 5 )   481 - 481   2004.9

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  • アムホテリシンBによる炎症性サイトカインの誘導とそのシグナル伝達経路

    松尾 謙一郎, 佛坂 斉祉, 岡田 幸雄, 坂井 詠子, 内藤 真理子, 大原 直也, 吉田 教明, 中山 浩次

    歯科基礎医学会雑誌   45 ( 5 )   334 - 334   2003.9

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  • 感染骨芽細胞から産生される4-1BBの解析-各種細菌に対する応答性の違いと標的細胞の検討

    斉藤 幹, 大原 直也, 佛坂 斉祉, 福本 敏, 藤原 卓, 中山 浩次

    歯科基礎医学会雑誌   45 ( 5 )   365 - 365   2003.9

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  • Porphyromonas gingivalisにおける線毛構成蛋白の輸送機構の解析

    庄子 幹郎, 内藤 真理子, 雪竹 英治, 大原 直也, 吉村 文信, 中山 浩次

    歯科基礎医学会雑誌   45 ( 5 )   362 - 362   2003.9

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  • 新しい結核ワクチンの開発とELISPOT assay(自動解析)を用いたT細胞活性化によるワクチン効果の解析

    田中 高生, 喜多 洋子, 井上 義一, 坂谷 光則, 岡田 全司, 桑山 さち子, 村木 裕美子, 稲永 由紀子, 金丸 典子, 橋元 里実, 高井 寛子, 渡邊 悠子, 岡田 知佳, 森 珠里, 石崎 邦子, 松本 久美, 岡 美穂, 黒川 恵理, 吉田 栄人, 金田 安史, 大原 直也, 内藤 真理子, 山田 毅, 松本 壮吉, Reed Steven, Skeiky Yasir, Gillis Steven

    結核   78 ( 3 )   278 - 278   2003.3

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  • MEK1阻害剤による破骨細胞の形成促進作用

    佛坂 斉祉, 坂井 詠子, 齋藤 幹, 大原 直也, 吉田 教明, 中山 浩次

    歯科基礎医学会雑誌   44 ( 5 )   495 - 495   2002.9

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  • Novel DNA and recombinant BCG vaccinations against tuberculosis by the augmentation of cytotoxic activity

    M Okada, S Yoshida, N Ohara, T Yamada, Y Kaneda, T Tanaka, Y Kita, S Kuwayama, Y Muraki, Y Inanaga, N Kanamaru, Y Inoue, M Matsumoto, K Kimura, M Sakatani, T Mori

    FASEB JOURNAL   16 ( 4 )   A308 - A309   2002.3

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  • DNA and recombinant BCG vaccination against tuberculosis by the augmentation of cytotoxic activity

    M Okada, T Tanaka, S Yoshida, N Ohara, T Yamada, Y Inoue, S Minamoto, M Sakatani, T Mori

    FASEB JOURNAL   15 ( 5 )   A1008 - A1008   2001.3

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  • ヒトマラリアの防御抗原を発現する組換えBCGワクチンの作製

    雪竹 英治, 大原 直也, 神原 廣二, 山田 毅, 松本 壮吉

    日本細菌学雑誌   56 ( 1 )   316 - 316   2001.2

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  • 抗酸菌抗原DNAワクチンとrBCGワクチンのモルモット免疫応答及び結核防御効果

    山本 三郎, 野島 康弘, 梅森 清子, 野間口 博子, 大原 直也, 山田 毅, 山本 十糸子, 佐藤 由紀夫, 松本 壮吉, 松尾 和浩

    日本細菌学雑誌   56 ( 1 )   315 - 315   2001.2

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  • 細胞内寄生菌感染骨芽細胞の遺伝子の解析

    大原 直也, 山田 毅

    歯科基礎医学会雑誌   42 ( 5 )   450 - 450   2000.8

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  • 細菌の人為的石灰化

    大原 直子, 大原 直也, 林 善彦

    歯科基礎医学会雑誌   42 ( 5 )   511 - 511   2000.8

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  • Analysis of CTL activity in the patients with multi-drug resistant tuberculosis and development of new vaccination by the induction of CTL using murine model.

    M Okada, Y Katayama, Y Inoue, M Yotsumoto, K Yasumitsu, S Hosoe, S Yoshida, N Ohara, T Yamada, M Sakatani, T Mori

    FASEB JOURNAL   14 ( 6 )   A1061 - A1061   2000.4

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  • 抗酸菌の重感染によるHIV-1複製亢進とサイトカインについて

    北浦 英樹, 大原 直也, 山田 毅

    日本細菌学雑誌   55 ( 2 )   211 - 211   2000.4

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  • 抗酸菌の主要抗原であるAntigen85をもちいたハンセン病予防ワクチンの開発

    山田 毅, 内藤 真理子, 松岡 正典, 野間口 博子, 大原 直也

    日本ハンセン病学会雑誌 = Japanese journal of leprosy   68 ( 1 )   53 - 53   1999.3

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  • マウスIL-2分泌recombinant BCG-膀胱癌細胞に対する抗腫瘍エフェクターの解析-

    山田 博, 松本 荘吉, 内藤 真理子, 大原 直也, 本田 毅, 松本 哲朗, 山下 優毅

    産業医科大学雑誌   21 ( 1 )   79 - 79   1999.3

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    Other Link： http://search.jamas.or.jp/link/ui/1999177582

  • 顎関節症患者の関節滑液中の抗体が認識する抗酸菌の44kDa蛋白質について

    安達 紀子, 松本 壮吉, 松尾 長光, 大原 直也, 内藤 真理子, 雪竹 英治, 山田 毅

    日本細菌学雑誌   54 ( 1 )   312 - 312   1999.2

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  • 分泌型リボゾーム蛋白質L7/L12の遅延型アレルギー反応について

    北浦 英樹, 大原 直也, 西山 毅, 木之本 雅通, 山田 毅

    日本細菌学雑誌   54 ( 1 )   318 - 318   1999.2

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  • シャペロン活性を示す結核菌リポゾ-ム蛋白質の解析

    大原 直也, 雪竹 英治, 田平 泰広〔他〕

    長崎大学熱帯医学研究所共同研究報告集   10   102 - 102   1999

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  • Hyperthermic OncologistsとThermal Phsiologistsによる総括的研究集会 13 抗酸菌のリボゾームに関与するストレス蛋白質の研究

    大原 直也, 田平 泰広, 山田 毅

    長崎大学熱帯医学研究所共同研究報告集   11   171 - 171   1999

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  • The binding mechanism between fibronectin and the mycobacterial immunodominant antigen, α antigen

    NAITO M., OHARA N., MATSUMOTO S., YAMADA T.

    21   314 - 314   1998.12

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  • A Ribosomal Protein possessing Chaperone Fanction

    OHARA Naoya, YUKITAKE Hideharu, KIMURA Makoto, YAMADA Takeshi

    21   444 - 444   1998.12

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  • 抗酸菌のストレス蛋白質-細胞外に分泌するHSPとリボゾ-ムに関わるHSP-

    大原 直也, 田平 泰広, 大原 直子

    長崎大学熱帯医学研究所共同研究報告集   9   109 - 109   1998.7

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  • ハンセン氏病予防ワクチンの開発

    山田 毅, 内藤 真理子, 大原 直也, 松本 壮吉, 松岡 正典, 野間口 博子

    日本ハンセン病学会雑誌   67 ( 1 )   63 - 63   1998.3

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  • マウス IL-2 分泌 recombinant BCG の作成および膀胱癌に対する抗腫瘍効果の検討 : 第86回日本泌尿器科学会総会

    山田 博, 松本 荘吉, 内藤 真理子, 大原 直也, 松本 哲朗, 山下 優毅, 山田 毅

    日本泌尿器科学会雑誌   89 ( 2 )   294 - 294   1998

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    DOI： 10.5980/jpnjurol.89.294_3

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  • BCG菌リボゾームに存在する熱応答性蛋白質の性質

    大原 直也, 大原 直子, 内藤 真理子, 山田 毅

    日本分子生物学会年会プログラム・講演要旨集   19   176 - 176   1996.8

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  • E Long-lasting immune response induced by recombinant Bacillus Calmette-Guerin (BCG) secretion system.

    Wada N., Ohara N., Kameoka M., Nishino Y., Matsumoto S., Nishiyama T., Naito M., Yukitake H., Okada Y., Ikuta K., Yamada T.

    Collected papers from the Institute of Immunological Science Hokkaido University   19   26 - 33   1996

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  • 結核発病における菌側の因子；抗酸菌の抗原の研究の意味

    山田毅, 大原直也, 松本壮吉, 松尾長光, 北浦英樹, 高野美貴子, 雪竹英治, 和田直子, 西山毅, 内藤真理子, 木ノ本雅道, 木村誠

    結核   70   639 - 644   1995

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  • Biochemical and immunological characterization of ribosomal fraction and culture filtrate from BCG Reviewed

    Yamada T, Ohara N, Matsumoto S, Matsuo T, Kitaura H, Takano M, Nishiyama T, Yukitake E, Miyazaki R, Nomaguchi H, Mastuoka M

    Proceedings to 30th Joint Reserch Conference on Leprosy and Tuberculosis   30   246 - 249   1995

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  • Cytotoxic T lymphocyte response in mice induced by a recombinant BCG Vaccination which produces an extracellular α antigen that @@S ' fused with the human immunodeficiency virus type 1 envelope immuno @@S dominant domain in the V3 loop.

    Kameoka Masanori, Nishino Yoshii, Matsuo Kazuhiro, Ohara Naoya, Kimura Takuro, Yamazaki Akihiro, Yamada Takeshi, Ikuta Kazuyosh

    Collected papers from the Institute of Immunological Science Hokkaido University   17   71 - 76   1994

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  • Study of a antigen from Mycobacterium intracellulare and use of PCR for the rapid identification of Mycobacterium intracellulare. Reviewed

    Kitaura H, Ohara N, Naito M, Nishiyama T, Wada N, Matsumoto S, Matsuo T, Hotokezaka H, Hayashida H, Kobayashi K, Yamada T

    Procceedings to 4th Western Pacific Congress on Chemotherapy and Infectious Diseases   10 ( 3 )   585 - 586   1994

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    DOI： 10.1006/bbrc.1993.2417

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  • Structure and immunological properties of major secreted antigen a and related antigens of mycobacteria. Reviewed

    Ohara N, Kitaura H, Naito M, Nishiyama T, Wada N, Matsumoto S, Matsuo T, Hotokezaka H, Hayashida H, Yamada T

    Procceedings to 4th Western Pacifuc Congress on Chemotherapy and Infectious Diseases   10 ( 3 )   628 - 629   1994

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  • Regulation of MPB70 gene expression between two major BCG substrains. Reviewed

    Matsuo T, Ohara N, Matsumoto S, Kitaura H, Naito M, Wada N, Nishiyama T, Hotokezaka H, Hayashida H, Mizuno A, Yamada T

    Procceedings to 4th Western Pacifuc Congress on Chemotherapy and Infectious Diseases   10 ( 3 )   590 - 591   1994

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Presentations

  • 速育化したBCGの宿主内での増殖 Invited

    大原直也, 阿戸学

    第100回日本結核・非結核性抗酸菌症学会学術講演会  2025.6.6 

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    Event date： 2025.6.6 - 2025.6.7

    Language：Japanese   Presentation type：Oral presentation (general)  

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  • Porphyromonas gingivalis ジンジパインによるphospholipase Cの活性化と歯周組織の炎症との関連性

    中山真彰, 内藤真理子, 中山浩次, 大原直也

    第65回歯科基礎医学会学術大会  2023.9.18 

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    Event date： 2023.9.16 - 2023.9.18

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  • 歯周病菌 Porphyromonas gingivalis のもつ タンパク質分解酵素ジンジパインの病原性 Invited

    大原直也

    第66回春季日本歯周病学会学術大会  2023.5.26 

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    Event date： 2023.5.26 - 2023.5.27

    Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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  • 薬剤耐性結核および非結核性抗酸菌症に対する治療薬開発

    瀧井猛将、岩月正人、山口智之、君嶋葵、渡邊善行、中山真彰、大原直也、浅見行弘

    日本薬学会第143年会  2023.3.28  日本薬学会

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    Event date： 2023.3.25 - 2023.3.28

    Language：Japanese  

    Venue：札幌市   Country：Japan  

  • Porphyromonas gingivalisジンジパインによるPLCを介したCOX-2発現とPGE2産生の分子機序

    中山真彰、山口智之、内藤真理子、大原直也

    第96回日本細菌学会総会  2023.3.16  日本細菌学会

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    Event date： 2023.3.16 - 2023.3.18

    Language：English   Presentation type：Poster presentation  

    Venue：姫路市   Country：Japan  

  • Mycobacterium aviumの酸性条件下での適応能の解析

    瀧井猛将、伊藤佐生智、大原直也、前田伸司、肥田重明

    第96回日本細菌学会総会  2023.3.16  日本細菌学会

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    Event date： 2023.3.16 - 2023.3.18

    Language：English   Presentation type：Poster presentation  

    Venue：姫路市   Country：Japan  

  • チミジル酸合成酵素ThyXの過剰発現はBCGの増殖を促進する

    竜門亜矢子、中山真彰、有村友紀、阿戸学、中島千絵、鈴木定彦、小崎弘貴、大原直也

    第69回日本細菌学会中国・四国支部総会  2016 

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    Event date： 2016.10.15 - 2016.10.16

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：岡山  

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  • PI3K/Akt経路に対するP. gingivalis ジンジパインの役割

    中山真彰、内藤真理子、中山浩次、大原直也

    第58回歯科基礎医学会学術集会・総会  2016 

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    Event date： 2016.8.24 - 2016.8.26

    Language：English   Presentation type：Poster presentation  

    Venue：札幌  

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  • Porphyromonas gingivalis ＥＣＦシグマ因子変異株における菌体表層性状の解析

    菊池有一郎、国分栄二、柴山和子、大原直也、中山浩次、石原和幸

    第58回歯科基礎医学会学術集会・総会  2016 

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    Event date： 2016.8.24 - 2016.8.26

    Language：English   Presentation type：Poster presentation  

    Venue：札幌  

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  • Mycobacterium smegmatis バクテリオファージの長期保存状態における生存率

    第68回日本細菌学会中国・四国支部総会  2015 

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Research Projects

  • 空間トランスクリプトーム解析による歯周炎の宿主－細菌叢構成細菌関係の時空間的理解

    Grant number：25K22687  2025.06 - 2027.03

    日本学術振興会  科学研究費助成事業  挑戦的研究(萌芽)

    大原 直也, 大野 充昭, 土佐 郁恵

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    Grant amount：\6370000 （ Direct expense: \4900000 、 Indirect expense：\1470000 ）

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  • 歯周病細菌主要病原因子ジンジパインの宿主直接作用と必須新奇オペロンの解明

    Grant number：24K02614  2024.04 - 2028.03

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    大原 直也

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    Grant amount：\18590000 （ Direct expense: \14300000 、 Indirect expense：\4290000 ）

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  • 細菌の酵素反応を基盤とした根面う蝕管理法の開発

    Grant number：23K09459  2023.04 - 2027.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    大原 直子, 松崎 久美子, 大原 直也, 吉山 昌宏

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

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  • Molecular mechanism of host cell response disruption and periodontal tissue destruction by proteases produced by periodontal bacteria

    Grant number：21K09842  2021.04 - 2026.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    中山 真彰, 大森 一弘, 大原 直也

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    Grant amount：\4030000 （ Direct expense: \3100000 、 Indirect expense：\930000 ）

    本研究の目的は，「歯周病原細菌と宿主細胞間で起こる感染現象の分子基盤を細胞・分子生物学的アプローチにより構築し，歯周病菌が産生する病原性プロテ アーゼの機能解析を行ない、歯周病の発症機序を解明する」ことである。本申請研究では歯周病細菌の感染による歯周病発症と病態形成機序を解明するために、 歯周病細菌Porphyromonas gingivalis (P. gingivalis)が産生する病原因子であるプロテアーゼ「ジンジパイン」に着目し、宿主細胞の主要なシグナル伝達経路 の撹乱機構を中心に分子解析を行なう。これまでの研究では、歯周病の発症におけるジンジパインの役割を調べるために、ジンジパイン完全欠損株とその野生株 を用いた感染実験による比較解析を行ない、歯周組織の炎症で発現がみられるCOX-2やPGE2の産生について調べた。P. gingivalisのLPSや線毛がCOX-2発現や PGE2産生に関与することは知られていたが、ジンジパインが発現誘導に関わる因子であることは報告がなかった。我々の結果から、本菌が産生するジンジパイン はLPSや線毛よりも強くCOX-2発現やPGE2産生を誘導することを明らかにした。またジンジパインによるCOX-2発現の分子機序について宿主細胞応答を調べたとこ ろ、ERKとIKKの2つのシグナル伝達経路の活性化とそれぞれ転写因子c-Jun/c-FosとNF-kBp65の活性化が重要であることを示し、さらには細胞内カルシウムの重要性も明らかにした。今後は、COX-2発現と PGE2産生 に繋がる上流因子の分子解析を行ない、ジンジパインが作用する細胞膜上の入り口となる因子の解析を行なう。

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  • アルカリ産生性アクチノマイセス属細菌を応用したう蝕管理法の確立

    Grant number：20K09939  2020.04 - 2023.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    大原 直子, 松崎 久美子, 大原 直也, 吉山 昌宏, 横山 章人

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    Grant amount：\4420000 （ Direct expense: \3400000 、 Indirect expense：\1020000 ）

    う蝕発症の直接的原因はプラーク内細菌が産生する有機酸の反応である。本研究では、細菌側へのアプローチにより細菌叢の病原性を制御すること、具体的には、アルカリ性を呈し酸を中和させる環境を創り出し、病原性の低い細菌叢へ誘導し毒性を軽減させることによるプラークコントロール法の確立を目的としている。
    アルギニンデイミナーゼシステム（ADS）は、アルカリ生成の主要経路の１つである。昨年度は、アクチノマイセス属の主要３菌種 Actinomyces viscosus、Actinomyces naeslundii、Actinomyces israeliiの培養環境中にアルギニンを添加することによる、アルギニン分解能およびアルカリ産生誘導について検討を行った。３菌種の中では、A. israeliiの反応が著明であり、トリプトン・イーストブロスに４％アルギニン塩酸を添加して２日間嫌気培養すると、アルギニン分解にともなうアンモニア産生により、アルカリ性の環境変化を誘導できることが示された。
    本年度は、３菌種から、アルギニンデイミナーゼ遺伝子のクローニングを行った。またmRNAを調整し、それらが発現していることを確認した。A. naeslundiiについては、２つの遺伝子がアルギニンデイミナーゼ遺伝子としてアノテーションされていたので、どちらも活性を有しているか、現在検討中である。その結果、どちらの遺伝子を使用するか見極める予定である。今後は、３菌種においてアルギニンデイミナーゼを高発現させ、プラーク環境のｐHコントロールを目指す。

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  • Elucidation of biofilm formation mechanism via signal transduction system of mycobacteria

    Grant number：19K08629  2019.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Nishiuchi Yukiko

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    Grant amount：\4420000 （ Direct expense: \3400000 、 Indirect expense：\1020000 ）

    Since one of the non-tuberculous mycobacteria, Mycobacterium avium subsp. hominissuis (MAH) forms a biofilm when exposed to hypoxia, we hypothesized that MAH senses hypoxia and expresses a group of biofilm-forming genes. To elucidate the mechanism of biofilm formation, we compared gene expression under hypoxia and atmosphere then identified a receptor gene MAV_RS11960, a two-component regulatory system that senses hypoxia. Comprehensive analysis of gene expression of over-expression strains of this gene and three environmental isolates with different ability of biofilm formation has been conducted and is ready for publication of results.
    The results of biofilm structure and virulence analysis of MAHs have been published, and these research results will provide the basis for prevention and treatment strategies by clarifying the mycobacterial dynamics not only within the environment but also within hosts.

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  • The mechanism of periodontal tissue destruction by proteases from periodontal bacteria Porpyromonas gingivalis.

    Grant number：17K11668  2017.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Nakayama Masaaki

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    The purpose of this study is to reveal the molecular mechanism of infection between periodontal pathogenic bacteria and host cells using cellular and molecular biological approaches, and to analyze the function of pathogenic proteases produced by periodontal pathogenic bacteria to clarify the pathogenesis of periodontal disease. In this study, we focused on gingipains, which are cysteine proteases, produced by Porphyromonas gingivalis (P. gingivalis), to elucidate the pathogenesis of periodontal disease infected with P. gingivalis. We examined the host cell response to the molecular mechanism of COX-2 expression by gingipains and showed that activation of two signaling pathways, ERK and IKK, and found that intracellular calcium is required for COX-2 expression and PGE2 production as the upstream factors.

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  • Understanding the pathogenicity of periodontal disease onset and systemic disease exacerbation caused by periodontal bacteria

    Grant number：17H04378  2017.04 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    OHARA Naoya

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    Grant amount：\17290000 （ Direct expense: \13300000 、 Indirect expense：\3990000 ）

    In this study, we focused on the proteases "gingipains", which is one of the virulence factors produced by the periodontal pathogen Porphyromonas gingivalis. We studied the molecular mechanism of COX-2 expression and PGE2 production induced by gingipains on P. gingivalis-infected monocyte/macrophage cells. In these events, we found the activation of ERK1/2 and IKK, activation of transcription factors AP-1 (c-Jun/c-Fos) and NF-κBp65. Furthermore, we clarified that gingipains-induced COX-2 expression and PGE2 production required the increase in calcium ion concentration due to intracellular influx from outside the cells.

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  • Analysis the virulence of Mycobacterium tuberculosis based of rapid-growing BCG

    Grant number：16K15277  2016.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    Ohara Naoya, KOSAKI Hirotaka, RYUMON Ayako

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    Grant amount：\3510000 （ Direct expense: \2700000 、 Indirect expense：\810000 ）

    Mycobacterium tuberculosis is an intracellular pathogen, has a remarkably slow growth rate, and survives long periods of time in the host. We found that overexpression of thyX in BCG (pthyX) resulted in accelerating its growth rate. We analyzed the gene expression profiles in pthyX using RNAseq. Several genes in folate metabolism pathway were up-ragulated in pthyX. We concluded that tetrahydrofolate is the key molecule in the control of the growth rate of slow-growing mycobacteria.

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  • Effects of Multilineage-differentiating stress-enduring (Muse) cells on brain damages induced by Shiga toxin 2 in vivo and in vitro

    Grant number：15K06801  2015.10 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Fujii Jun, DEZAWA Mari

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    Non-Muse cells are normal bone marrow mesenchymal stem cells minus Muse cells. NOD-SCID mice were infected with an injection directly into the stomach, with a bacterial suspension of STEC O111 1010 CFU (100% mortality). On day 2 after inoculation of STEC, bone marrow-derived Muse cells or non-Muse cells (bone marrow-MSCs other than Muse cells) were administered intravenously from the tail vein of the mouse model. An intravenous injection of human Muse cells had a strong effect in reducing the mortality rate (p<0.01) in the oral infection mouse model with STEC O111. In vitro experiment, reactivity of GFAP was maximized when 10 ng/ml of Stx2 and 1 &micro;g/ml were exposed for a 12 h period. On greater observation many GFP-Muse cells were had attached to reactive astrocytes and some Muse cells surrounded astrocytes, and it seems that they may have killed the reactive astrocytes. In this microarray analysis, we discovered the factor X that may be involved in the reactive astrocytes.

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  • Development of a novel root caries treatment by bacterial inactivation factor

    Grant number：15K11113  2015.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    OHARA Naoko

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    Grant amount：\4680000 （ Direct expense: \3600000 、 Indirect expense：\1080000 ）

    In this study an in vitro root caries induction model system was constructed to develop a new treatment for inhibition of progression of root caries. Using this model system, we investigated the influence on root caries progression bacteria dynamics of the carious lesion by strains and the culture conditions of cariogenic bacteria. The results showed that three Actinomyces species, A. naeslundii, A. viscosus, and A. israelii, possessed different characteristics on the pathology and the mechanisms of root caries progression.

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  • Development of new periodontal disease prevention method using ECF sigma factors of periodontal pathogenic bacteria

    Grant number：26463171  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    KIKUCHI YUICHIRO, NAKAYAMA Koji, OHARA Naoya

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    Grant amount：\4940000 （ Direct expense: \3800000 、 Indirect expense：\1140000 ）

    Porphyromonas gingivalis has been recognized as a major pathogen in chronic periodontitis. Some bacteria utilize sigma factor proteins of the extracytoplasmic function (ECF) subfamily. In this study, we have investigated the ECF sigma factors in P. gingivalis to determine their roles in this bacterium. Insertional mutagenesis was used to create P. gingivalis mutants lacking ECF sigma factors of strain ATCC 33277. The PGN_0274 mutant showed no hemagglutination activity and much less aggregation. The PGN_0274 mutant displayed an increase susceptibility to ampicillin compared with the wild type strain. TEM images revealed that PGN_0274 mutant formed numerous outer membrane vesicles at the cell surface. These results indicated that PGN_0274 ECF sigma factor is important for bacterial surface-associated activities, including autoaggregation, hemagglutination, vesicle formation and ampicillin susceptibility.

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  • Molecular mechanisms of periodontal diseases and systematic diseases associated with periodontal diseases by periodontal pathogens

    Grant number：26293401  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    OHARA Naoya, TAGUCHI Yuko, KANO Konami

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    Grant amount：\16510000 （ Direct expense: \12700000 、 Indirect expense：\3810000 ）

    Periodontal diseases are chronic oral bacterial infectious diseases. In our study, Porphyromonas gingivalis, which is one of major oral pathogens, produces cysteine proteases called as gingipains. Gingipains attenuate PI3K/Akt signaling pathway, and which is associated with their protease activity from extracellular interaction without invasion of this organisms. Moreover, several downstream proteins of Akt, which are GSK3, mTOR, Bad, PRAS40, and MDM2, are also changed the their phosphorylation level by gingipains in gingival epithelial cells. On the basis of the results, their physiological activity might be dysregulated by gingipains in parallel with inactivation of PI3K/Akt in the cells.

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  • Analysis of mechanism of T cell targeting into Mycobacterium tuberculosis-infected lung and development of new lung-targeting vaccine strategy

    Grant number：25293105  2013.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Matsuzaki Goro, Umemura Masayuki, Ohara Naoya, Arakawa Takeshi

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    Grant amount：\17550000 （ Direct expense: \13500000 、 Indirect expense：\4050000 ）

    Analysis of chemokine receptors on CD4+ T cells migrated in the Mycobacterium tuberculosis-infected lung showed expression of CXCR3, but anti-CXCR3 mAb-treated mice suggested dispensable role of CXCR3 in the T cell migration. On the other hand, involvement of chemokines are suggested by enhancement of vaccine efficacy of BCG after inoculation of IL-17-inducing vaccine in the lung. Fluorescent protein-expressing M. tuberculosis was also developed to visualize interaction of T cell migration to infected microfoci by using fluorescent microscope incubator system introduced in P3 laboratory.

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  • ＴｒａＳＨ法による歯周病原細菌の宿主細胞内防御系からの回避機構の解明

    Grant number：24592765  2012.04 - 2015.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    井上 哲圭, 中山 真彰, 大原 直也

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    Grant amount：\5330000 （ Direct expense: \4100000 、 Indirect expense：\1230000 ）

    Porphyromonas gingivais (Pg) ATCC 33277株のトランスポゾン変異株ライブラリーのスクリーニングによって新たに見出された本菌の宿主細胞内感染に関わるx遺伝子に関して、本年度の研究により、x遺伝子は本菌の主たる病原因子であるプロテアーゼ（ジンジパイン）の分泌に関わることが明らかとなった。すなわち、新規にx遺伝子の遺伝子欠損株を作製し、血液寒天培地上で培養すると、親株では菌体外に分泌されたジンジパインの作用により黒色集落が形成されるのに対し、x遺伝子欠損株では菌体外ジンジパイン欠損株の特徴である白色集落が形成された。そこで、親株、x遺伝子欠損株およびそのx遺伝子相補株の菌体外ジンジパイン活性の測定を行った。本菌は2種のArg-ジンジパインと1種のLys-ジンジパインを産生する。上記3株の全菌体および培養上清を調製し、各々のジンジパインに特異的な蛍光基質を用いて活性測定を行った。その結果、x遺伝子産物は、3種のジンジパインのいずれの分泌にも関与していることが判明した（第56回歯科基礎医学会にて発表）。さらに、ATCC 33277株のゲノム上にはx遺伝子のorthologが2個存在することもわかった（x2, x3遺伝子）。これらの遺伝子はPgの他の菌株はもとより、近縁のBacteroides属菌種を含む様々な菌種、さらに腸内細菌においてもhomologが広く存在することがわかってきた。このことは、細菌細胞におけるこのx遺伝子の普遍的な機能を示唆しているとも考えられるが、例えば大腸菌においては、菌体外物質の分泌とは異なる機能を有することが報告されており、Pgにおけるx遺伝子産物の役割はマルチファンクショナルなものである可能性も考えられた。今後、Pgにおけるx遺伝子の病原性における役割を検討し、本菌の病原メカニズムの全貌の解明に貢献していく。

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  • Kinetic analysis of cariogenic bacteria on root dentin caries

    Grant number：24592866  2012.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    OHARA NAOKO, YOSHIYAMA Masahiro, OHARA Naoya

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    Grant amount：\5460000 （ Direct expense: \4200000 、 Indirect expense：\1260000 ）

    In this study, root caries-induced model was constructed in vitro using the oral streptococci or Actinomyces species. With respect to the change of bacterial species and culture conditions, the penetration depth and dentinal tubules diameter into the dentinal tubules in the lesion of root surface caries were analyzed. As the results, it was indicated that the number of colonization and dentin invasion depended on bacterial species. These findings suggest that bacterial infection of root dentin caries are heavily involved in dental caries pathology.

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  • Molecular imaging analysis of the antitumour activity of 5-fluorouracil combine with Mycobacterium bovis bacillus Calmette-Guérin (BCG) in the mouse oral cancer model.

    Grant number：24593030  2012.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    YANAGI Yoshinobu, TSUJIGIWA Hidetsugu, UNETSUBO Teruhisa, OHARA Naoya, NAGATSUKA Hitoshi

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    Grant amount：\5200000 （ Direct expense: \4000000 、 Indirect expense：\1200000 ）

    Our aim was to investigate the adjuvant potential of BCG combined with 5-FU for oral cancer. Then, we compared 18F-FDG PET/CT-based molecular imaging evaluation, with corresponding groupwise overall survival, tumor growth and metastasis. Sq-1979 cheek cancer cells were injected subcutaneously into the flank in C3H/HeN mice. After certain growth, tumors were resected and mice were weekly treated with BCG (Tokyo strain; 1 × 106 CFU/mouse) and/or 5-FU. The mice were randomized to four groups. 5-FU along with BCG treatment results in a reduction of recurrence and significantly improved survival. The effects of treatment on 18F-FDG uptake were also studied with those had locally metastatic tumors. This analysis revealed that 5-FU-, 5-FU/BCG-, and BCG-treatment resulted in a reduction of 18-FDG uptake within locally metastatic tumor compared with non-treated mice group. Interestingly, 18F-FDG PET imaging confirmed decreased metabolism even in the xenografts following BCG single treatment.

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  • The application of bacterial biomineralization to sealed restoration

    Grant number：24659847  2012.04 - 2014.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    YOSHIYAMA MASAHIRO, NISHITANI Yoshihiro, OHARA Naoko, OHARA Naoya

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    Grant amount：\3640000 （ Direct expense: \2800000 、 Indirect expense：\840000 ）

    We used Corynebacterium matruchotii as test bacteria, and we cultured bacteria to the agar medium and a liquid medium which added calcium chloride. We set a period of an instruction and the mineral formation with 2-12 months and observed the formation of the calcium deposition.
    As a result, we observed the mineral formation in the liquid culture from two months, and the calcification in the cell body became clear with the increase between the mineral formative periods. We did not accept the clear calcium deposition formation in the solid culture. C. matruchotii produced bacterial biomineralization by culturing it in calcium-rich environment. In addition, we got a conclusion that the instruction in the liquid medium is desirable for an instruction method.

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  • 新興・再興感染症を標的としたプライムブーストワクチンの開発と有効性・安全性評価システムの構築

    Grant number：KHC1016  2011.04 - 2012.03

    Japan Health Science Foundation  政策創薬総合研究事業  BCGベクターに有用な日本株BCGの特性に関する研究

    山本三郎, 松尾和浩, 矢野郁也, 網康至, 内藤誠之郎, 瀧井猛将, 藤原永年, 松本壮吉, 大原直也, 後藤義孝, 加藤洋行, 前山順一

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  • receptor

    Grant number：23590532  2011 - 2013

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    OKADA Masaji, SUZUKI Katsuhiro, TSUYUGUCHI Kazunari, YOSHIDA Shigeto, OHARA Naoya

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    Grant amount：\5330000 （ Direct expense: \4100000 、 Indirect expense：\1230000 ）

    Cytotoxic T cells against M. tuberculosis are one of most important immune cells for the protection of tuberculosis infection in human.
    (1)It was demonstrated first that HSP65 DNA+IL-12 DNA vaccine (HSP65 vaccine) and 15K Granulysin vaccine exerted the activity of cytotoxic T cell differentiation factor in the present study. (2)Therefore, the presence of the receptor for granulysin was strongly suggested. We are now isolating the granulysin receptor. (3)We found granulysin-granulysin positive feedback loop. Granulysin was produced from CTL, and granulysin act on the differentiation of CTL. (4)HSP65 vaccine and Granulysin vaccine exerted synergistic therapeutic efficacy against TB infection in mice, and showed the synergistic differentiation of CTL.

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  • Investigation on the automation and speeding up ofmeasurement of the plasma IgG antibody titers against periodontopathic bacteria

    Grant number：22390397  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    TAKASHIBA Shogo, MAEDA Hiroshi, OHARA Naoya, NOZOE Mikio

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    Grant amount：\13000000 （ Direct expense: \10000000 、 Indirect expense：\3000000 ）

    It is difficult to measure serum IgG antibody titers against periodontopathic bacteria stably and speedily. In this study, we havesucceeded to select antigens of Porphyromonas gingivalisfor effective serodiagnosis of periodontitis and synthesized 16 antigens. In addition, we confirmed the reaction against serum obtained from periodontal patients. Inthe future, we will identify antigens for effective serodiagnosis and establish the automatic diagnostic system.

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  • Study on the survival strategies for periodontal bacteria in host cells and their role in the pathogenesis of periodontal diseases

    Grant number：22390342  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    OHARA Naoya, NAKAYAMA Masaaki, OHARA Naoko

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    Grant amount：\19500000 （ Direct expense: \15000000 、 Indirect expense：\4500000 ）

    Porphyromonas gingivalisis the major periodontal pathogens. 1) We identified P. gingivalis genes required for survival in the host cells using newly constructed transposon mutagenesis library of P. gingivalis. 2) We found the novel cellular events in host epithelial cells by challenging of P. gingivalis. Akt and its substrates were dephosphorylated by P. gingivalis infection. These results indicated that P. gingivalis-infection may affect cellular functions including apoptosis, glucose metabolism and cell development in host cells by inactivating the PI3K/AKt pathway.

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  • Development of prevention and treatment methods for infection by enterohemorrhagic Escherichia coli O157 based on bio-protect ive mechanisms

    Grant number：22590256  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    KOBAYSHI Hideyuki, MORII Hiroyuki, FUJII Jun

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    We have developed a novel vaccine using a recombinant BCG expressing the verotoxin B-subunit. The immunized mice with this vaccine survived longer than the nonvaccinated mice, confirminging the validity of this vaccine.
    On the other hand, the expression of various bioactive peptides in the brain microvascular endothelial cells was changed by verotoxin. The expression of cytokines was increased suggesting that the interaction between brain microvascular endothelial cells and the leukocytes was changed by verotoxin.

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  • Analysis of molecular mechanism of bone metabolism disruption by bacterial infection

    Grant number：19592118  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    OHARA Naoya, NAKAYAMA Koji, OKABE Mayuko, NAKAYAMA Koji, OKABE Mayuko

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    細菌感染による骨破壊のメカニズムを明らかにする目的で、歯周病原細菌Porphyromonas gingivalisとBCGを用い、その感染による破骨細胞分化への影響を調べた。M-CSF/RANKLで誘導される破骨細胞の分化初期にP. gingivalisあるいはBCGが感染するとその分化は抑制されたが、これは破骨細胞と異なる細胞へ分化の方向性が変化したことによることが示唆された。このときに自然免疫系のToll-like receptor(TLR)からのシグナル以外のシグナルが関与していることが示唆された。インターフェロンの関与は認められなかった。破骨細胞分化後期に細菌が感染した場合には破骨細胞の形成が促進された。この促進にはTLR2あるいはTLR4、その下流のMyD88からのシグナルが破骨重要であることが示唆された。

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  • Hydrogen Sulfide Production from Cysteine and Homocysteine by Periodontal and Oral Bacteria

    Grant number：19592409  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    YOSHIDA Yoshida, TAKEHARA Tadamichi, ANSAI Toshihiro, AWANO Shuji, SOH Inho, HAMASAKI Tomoko, NAKAYAMA Koji, OHARA Naoya

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    各種口腔細菌の培養液を用いて、ホモシステインおよびシステインを基質とした、ホモシステイン分解活性およびシステイン分解活性を各々の基質について測定した。菌数が既知の菌液のホモシステイン分解活性あるいはシステイン分解活性を測定することにより、単位菌数あたりの酵素活性を測定した。また、ホモシステインおよびシステインを基質とした場合のそれぞれの分解活性の高い口腔細菌種を同定した。また、ホモシステインおよびシステインの分解産物である硫化水素を測定することにより口腔細菌の迅速検出系を構築し、その評価を行った。

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  • The study of the mechanism of therapeutic efficacy of novel vaccines on Tuberculosis-infection and the induction of cytotoxic T cells by the vaccines

    Grant number：18390138  2006 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    OKADA Masaji, YOSHIDA Shigeto, OHARA Naoya, SUZUKI Katsuhiro, INOUE Yoshikazu, TSUYUGUCHI Kazunari

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    Grant amount：\17440000 （ Direct expense: \14500000 、 Indirect expense：\2940000 ）

    (1)We have developed a novel therapeutic tuberculosis (TB) vaccine ; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-envelope (HSP65+IL-12/HVJ). This vaccine induced CD8^+ cytotoxic T-cell specific for TB antigen.
    (2)This vaccine exerted therapeutic efficacy in the TB-infected cynomolgus monkeys as well as mice.
    (3)Granulysin augmented in vitro and in vivo induction of CTL. Thus, it was demonstrated that granulysin is CTL differentiation factor. Furthermore, in the presence of IL-6 or IL-2 the in vitro and in vivo induction by granulysin was synergistically enhanced.
    (4)We established granulysin transgenic mice.

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  • Study for gignipain-related adhesins of Periodontal pathogen, Porphyromonas gingivalis for its platelet aggregation activity

    Grant number：18592005  2006 - 2007

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    NAITO Mariko, SAKAI Eiko, YOSHIMURA Astutoshi, OHARA Naoya, NAKAYAMA Koji

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    Grant amount：\4010000 （ Direct expense: \3500000 、 Indirect expense：\510000 ）

    The periodontal pathogen Porphyromonas gingivalis has the ability to aggregate human platelets. P. gingivalis is highly proteolytic, has major protainases, gingipains. The gingipain genes are consisting of N-terminal proteolytic domain and C-terminal adhesin domains. Gingipain derived adhesin, Hgp44 is the key molecule for P gingivalis-induced platelet aggregation in human platelet-rich plasma. The study of truncated recombinant Hgp44 protein shows that the active site is the N-terminal part (1-101 aa). This site is also important for Hgp44-induced erythrocyte aggregation. Hgp44 binds to glycophorin on human erythrocyte, also to human oral epithelial cells. The adhesin domains are also essential for gingipains to suppress of IL-8 induction from human oral epithelial cells. The receptor activator of nuclear factor-LIB (RANKL)-induced osteoclastogenesis from bone marrow is inhibited by one of adhesin domain, HbR. Furthermore the gingipains affect bacteria-host interactions and may directly promote apoptosis. We defined the complete genome sequence of strain ATCC 33277 that is the type strain of P gingivalis. The newly 4 genes find on genome of ATCC 33277 that encoded the adhesin domains of gignipains. Those genes lost the proteolytic domains. Some genes are also defined that transports gingipain to bacterial surface and controls expression of gignipains. Those transporters suggested the unique secretion system for gignipain. Those results indicates that gingipain derived adhesins has various biological activity in host cells. Such complex activity might to help the microorganism exist long in the niche. Clearly, a detailed knowledge of how gignipain, also its adhesin domain protein, regulates host cells will shed important light on the mechanism of tissue damage in gingivitis and may provide a pharmacological regimen to control the infection.

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  • Molecular Mechanisms of Interaction between Periodontitis and Cardiovascular and Bone Metabolic Disorders

    Grant number：17209057  2005 - 2007

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

    NAKAYAMA Koji, IKEDA Toru, YOSHMURA Atsutoshi, SAKAI Eiko, NAITO Mariko, AMANO Atsuo

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    Grant amount：\49530000 （ Direct expense: \38100000 、 Indirect expense：\11430000 ）

    The periodontopathic bacterium Porphyromonas gingivalis has the ability to agglutinate human erythrocytes. We found that the Hgp44 domain protein, which is encoded by gingipain-related genes of P. gingivalis, can agglutinate erythrocytes by using a recombinant Hgp44 protein. The target molecule on the cell surface of erythrocytes against Hgp44 was found to be glycophorin. Also, we found that a peptide encoded by a DNA region backward of the region encoding Hgp44 has the inhibitory effect on the Hgp44-mecliated hemagglutination.
    P. gingivalis cell-induced platelet aggregation is particularly important for interaction between periodontal disease and cardiovascular disease. It has been believed that P. gingivalis-mediated platelet aggregation is caused by activation of PAR receptor on platelets by Arg-gingipain. However, we found that P. gingivalis cell-mediated platelet aggregation does not depend on Arg-gingipain but Hgp44 protein on the bacterial cell surface, anti-P. gingivalis antibody in serum, and FcγRIIa and GPIlb/IIIa on platelets.
    Alveolar bone resorption is one of the characteristic symptoms in periodontal disease, which results in tooth loss. Tooth loss causes loss of the gingival crevice that is an anatomical niche for periodontal pathogens such as P. gingivalis. We found that culture supernatants of P. gingivalis have the ability to inhibit in vitro osteoclastogenesis from bone marrow macrophages and determined that a hemoglobin receptor protein (HbR), which is a major protein in the culture supernatants, is the inhibitor to osteoclast formation. The HbR protein inhibited RANKL-induced Akt phosphorylation and expression of NFATc1 and c-Fos.

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  • P.gingivalisの生体内環境における病原性発現調節機構の解析

    Grant number：17019057  2005

    日本学術振興会  科学研究費助成事業  特定領域研究

    大原 直也, 中山 浩次

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    Grant amount：\3000000 （ Direct expense: \3000000 ）

    Porphyromonas gingivalis(P.gingivalis)はもっとも有力な歯周疾患の原因菌と考えられている。また近年では全身の慢性炎症性疾患との関連性も強く疑われている。宿主内で多く発現している遺伝子が病原性に関わっている可能性が高い。BALB/cマウス背部皮下に埋入したコイル内腔にP.gingivalis W83株を接種し、6時間後に菌体を回収した。回収された菌体で発現量の上昇した蛋白質の中で3種、immunoreactive 61 kDa antigen PG91、DNA-binding response regulator RprY、TPR domain proteinに着目し、W83株を用いてそれぞれの遺伝子変異株を作製した。RprYは2成分制御系の調節蛋白質分子であり、マウスを用いて各変異株の病原性を検討したところ、PG91欠損株の病原性は親株(野生株)との間に差が見いだせなかったが、RprY、TPR domain proteinそれぞれの欠損株では病原性が顕著に減弱していた。RprYは2成分制御系の調節蛋白質分子であり、またTPR domainは真核細胞においてシャペロン分子の足場のような役割をしていることから、両者が複数の病原性因子の調節に関わっていることが示唆される。
    ゲノム情報からのアプローチとしてW83株とATCC33277株で異なっている莢膜合成に関する酵素の遺伝子欠損株を作製した。また33277株をベースとしてトランスポゾンTn4351の挿入変異株ライブラリーを作製した。これらの株について今後病原性の検討をおこなう必要がある。

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  • 口腔慢性細菌感染の心血管系および骨代謝系への影響とその病原因子に関する研究

    Grant number：16017282  2004 - 2005

    日本学術振興会  科学研究費助成事業  特定領域研究

    中山 浩次, 大原 直也, 内藤 真理子, 庄子 幹郎

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    Grant amount：\11600000 （ Direct expense: \11600000 ）

    本年度の当初の実験計画ではP.gingivalisをApoE欠損マウスの口腔内や静脈内に接種して心血管疾患モデルを作製し、いろいろなP.gingivalis変異株を用いた実験を行う予定であったが、ApoE欠損マウスの米国からの購入がカルタヘナ議定書締結の関係で9月まで遅れ、現在、頭数を増やす努力を行っている。
    一方、骨代謝系へのP.gingivalisの影響については以下の結果が得られた。P.gingivalisを血液寒天培地で培養した際にその菌体表面に顕著に発現が認められる19kDaのタンパク質(HbR)は、ヘモグロビンとの結合性を有し、P.gingivalisにおけるヘムの獲得・蓄積に関与していることで知られており、rgpA、kgp、およびhagA遺伝子内にドメインタンパク質としてコードされている。マウス骨髄細胞由来の破骨細胞前駆細胞にM-CSF、RANKLと共に組換えHbRタンパク質を添加して5日間培養するとTRAP陽性多核細胞の形成が抑制されることをすでに報告した。今回、破骨細胞前駆細胞にP.gingivalisの長期培養上清中にHbRタンパク質が多量に含まれていること、また、この培養上清を添加すると破骨細胞前駆細胞からのM-CSF/RANKL誘導性破骨細胞形成が抑制されることがわかった。さらに、組換えHbRタンパク質を2日目以降に添加した場合には抑制効果が認められなかった。細胞内シグナルでは組換えHbRタンパク質添加によりRANKLで誘導されるAktのリン酸化や、NFATc1及びc-Fosの発現が抑制された。組換えHbRタンパク質添加はIFN-βの発現を誘導したが、その誘導レベルは破骨細胞分化を抑制する量には達していないことがわかった。

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  • Study on the oxidative stress responses of a major periodontopathogenic bacteria

    Grant number：16591831  2004 - 2005

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    OHARA Naoya, NAKAYAMA Koji, NAITO Mariko, SHOJI Mikio

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    Grant amount：\3600000 （ Direct expense: \3600000 ）

    Inspection of genomic DNA sequence of the oral anaerobe Porphyromonas gingivalis reveals that the microorganism possesses the peroxide-sensing transcription activator OxyR, but not the superoxide-sensing transcription factor SoxR. Oxidative stress-responsive proteins in the microorganism were investigated using two dimensional gel electrophoresis and it was found that two proteins, SOD and AhpC were predominantly upregulated in oxidative conditions. In P. gingivalis oxyR mutant these two proteins were not induced by treatment with hydrogen peroxide under aerobic conditions. P.gingivalis sod and ahpC were positively regulated by OxyR. Putative -35 boxes of these promoters were found immediately adjacent to their putative OxyR binding sequences. Moreover, the promoter regions of sod and ahpC had the ability to bind P.gingivalis OxyR protein. These results demonstrate that P.gingivalis sod is one of the OxyR regulons, suggesting that OxyR functions as an intracellular redox sensor rather than a peroxide sensor in this organism.
    The new protein (UstA) was also identified in this study. Expression of UstA was upregulated in stationary phase or by exposure to atmospheric oxygen. The UstA-encoding gene (ustA) was located upstream of a homologue of the usp gene. The ustA gene appeared to be transcribed in a monocistronic fashion. The ustA mutant grew slower than the wild type parent strain, resulting in a lower yield in stationary phase. Furthermore, in this mutant, the expression levels of SOD, Tpr, and Trx were markedly higher than those in the wild type. The ustA mutant was more resistant to diamide, a thiol-specific oxidant, than the wild type. In addition, the ustA mutation suppressed hypersensitivities of the oxyR mutant to diamide,. metronidazole, and mitomycin C. These results suggest that UstA may play a significant role in oxidative stress responses in the bacterium.

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  • 歯周病原細菌菌体表面タンパクの心血管系および骨代謝系に及ぼす影響

    Grant number：15019078  2003

    日本学術振興会  科学研究費助成事業  特定領域研究

    中山 浩次, 庄子 幹郎, 内藤 真理子, 大原 直也

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    Grant amount：\5900000 （ Direct expense: \5900000 ）

    1)P.gingivalisの血小板凝集活性について各種の変異株を用いた解析からrgpA,kgp,hagA遺伝子にコードされているadhesin domainタンパクがプロテアーゼによってプロセスされた形で菌体表面に発現していることが必須であることが示唆された。このadhesin domainタンパクを介した血小板活性化には血漿成分を必要とすること、血小板表面のGPIbレセプターが活性化に関与することがわかった。また、従来、本菌のRgpプロテアーゼがPARレセプターを介して血小板を活性化するといわれているが血漿成分が存在する環境ではほとんどRgpプロテアーゼによる活性化がみられないことがわかった。
    2)BCG菌をosteoblastic cellに感染させるとTNFaレセプターファミリーの一つである4-1BBの発現が亢進することを見いだした。この発現亢進は大腸菌、ネズミチフス菌、黄色ブドウ球菌の感染および大腸菌由来LPSや熱処理死菌BCG菌でも生じることがわかった。4-1BBのリガンド分子は骨髄細胞、マクロファージ様株化細胞に発現していることから4-1BBの破骨細胞分化への影響を骨髄細胞を用いて解析した。その結果、固層化した4-1BBは1ng/mlという低濃度でもRANKL/M-CSF誘導破骨細胞分化を抑制することがわかった。さらにRANKL/M-CSFによるI-kB,ERK1/2,p38,JNKのリン酸化には4-1BB処理は影響しなかったがAKTのリン酸化は4-1BB処理により抑制されることがわかった(Saito et al.,J.Biol.Chem.,in press)。
    3)全骨髄細胞を用いたM-CSF/RANKL誘導性破骨細胞分化システムにおいてはIL-12はアポトーシスは起こさないが破骨細胞分化を抑制することがわかった。この抑制作用は破骨細胞前駆細胞に直接IL-12が作用するのではなく、IL-12の働きで他の骨髄細胞から液性因子を放出させることにより起こることがわかり、この液性因子の有力な因子がIFN-gであることが抗IFN-g抗体やIFN-g receptor knockout mouse実験から示唆された。また、IFN-gの産生細胞は非T細胞系である可能性が示唆された(Nagata et al.,Bone,2003;33:712-32)。

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  • Pest-sequencing analysis of periodontal pathogen Porphyromonas gingivalis : expression of its proteins by oral environmental fectors.

    Grant number：14370585  2002 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    NAKAYAMA Koji, OHARA Naoya, NAITO Mariko, SHOJI Mikio

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    Grant amount：\13900000 （ Direct expense: \13900000 ）

    Porphyromonas gingivals, an obligate anaerobic bacterium, is implicated as a major pathogen in the development and progression of chronic periodontitis. Although expression of several virulence factors of the bacterium has been found to be affected by environmental stress such as entrance into the stationary growth phase and heat, there is relatively little information on the mechanisms that may operate in the bacterium in response to environmental stress. In this study, we investigated the new protein (UstA) that was initially identified following the two dimensional gel analysis. Expression of UstA was upregulated in stationary phase or by exposure to atmospheric oxygen. N-terminal sequencing and database analysis with the P.gingivalis genome sequence revealed that the UstA-encoding gene (ustA) was located upstream of a homologue of the usp gene encoding the universal stress protein on the chromosome. The ustA gene appeared to be transcribed in a monocistronic fashion as revealed by primer extension and Northern blot analysis. To elucidate the role of UstA in the bacterium, chromosomal mutants carrying a disruption of the ustA gene were constructed. The ustA mutant grew slower than the wild type parent strain in rich medium, resulting in a lower yield in stationary phase. Furthermore, in this mutant, the expression levels of the P.gingivalis homologues of superoxide dismutase, thiol peroxidase, and thioredoxin were markedly higher than those in the wild type especially in stationary phase. The ustA mutant was more resistant to diamide, a thiol-specific oxidant, than the wild type. In addition, the ustA mutation suppressed hypersensitivities of the oxyR mutant to diamide, metronidazole, and mitomycin C. These results suggest that UstA may play a significant role in oxidative stress responses in the bacterium.

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  • Establishment of Novel (DNA-recombinant BCG-, and fusion protein-)vaccination against Tuberculosis and analysis of novel differentiation mechanism of cytotoxic T cell

    Grant number：14570294  2002 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    OKADA Masaji, OHARA Naoya, YOSHIDA Shigeto, SUZUKI Katsuhiro, INOUE Yoshikazu, MINAMOTO Seijiro

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    Grant amount：\3200000 （ Direct expense: \3200000 ）

    〔Abstract〕
    1.The production of cytotoxic T cell differentiation factors (IL-6,IL-2,and IFN-Y,) were inhibited in the culture supernatants from patients with tuberculosis. Furthermore, it was demonstrated that the expression of granulysin (cytotoxic protein against tuberculosis) protein in CD3^+ CD8^+ CTL from TB patients was suppressed in comparison with the granulysin expression on CD8^+ CTL from healthy volunteers.
    2.Two novel TB vaccines ; a DNA vaccine combination expressing mycobacterial heat shock protein 65(HSP65) and interleukin-12(IL-12) by using the hemagglutinating virus of Japan(HVJ)-liposome (HSP65+IL-12/HVJ), have been developed. These vaccines provide remarkable protective efficacy in mouse and guinea pig models, as compared to the current by available BCG vaccine.HSPGS DNA+IL-12 DNA vaccination were 100 fold more efficient than parental BCG Tokyo vaccination, on the elimination of M. TB in lungs, liver, and spleen of BALB/c mice. In the present study, our studies were extended to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis, to evaluate the HSP65+IL-12 vaccine. Vaccination with HSP65+IL-12 DNA provided better protective efficacy as assessed by the Erythrocyte Sedimentation Rate, chest X-ray findings, body weight and immune responses (IFN-y, IL-2, IL-6 production, and lymphocyte proliferation of cynomolgus monkey), than BCG. Most importantly, HSP65+IL-12 DNA vaccine resulted in an increased survival for over a year. This is the first report of successful DNA vaccination against M. tuberculosis in the monkey model.

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  • Investigation of New Drugs that Inhibit Acquisition of Iron from Oral Environments in the Periodontopathogen Porphyromonas gingivalis.

    Grant number：13557149  2001 - 2003

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    NAKAYAMA Koji, TERAGUCHI Susumu, SHIMOKAWA Osamu, OHARA Naoya

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    Grant amount：\12000000 （ Direct expense: \12000000 ）

    The oral anaerobic bacterium Porphyromonas gingivalis is implicated as an important pathogen for periodontitis. A non-iron metalloporphyrin, indium-protoporphyrin (In-PPIX) was examined for antibacterial effects on P. gingivalis. In-PPIX showed growth inhibition of P. gingivalis in a dose-dependent fashion. An ihtB mutant of p. gingivalis was more resistant to In-PPIX than the wild type parent, while an hmuR mutant was more sensitive, indicating that In-PPIX might be incorporated by the IhtB-mediated iron uptake pathway. An sod mutant of P. gingivalis showed almost the same sensitivity to In-PPIX, which was contrast with the finding that E. coil SOD-null mutant shows hypersensitive to galium-protoporphyrin. Moreover, P. gingivalis dps mutant showed more resistant to In-PPIX than the wild type parent, suggesting that Dps protein which is one of iron-containing proteins might be related with In-PPIX toxicity. We already found that lactoferrin and its active peptide domain, lactoferricin have the ability to inhibit growth of P. gingivalis. Lactoferrin removes the hemoglobin receptor protein (HbR) from the P. gingivalis cell surface with the result of growth inhibition. This inhibition system seems to be different from that of In-PPIX, suggesting that use of both chemicals may show a synergistic effect on growth of P. gingivalis.

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  • Identification of HLA-restricted cytotoxic T cell epitopes of Mycobcaterium tuberculosis for developing epitope vaccines

    Grant number：13670268  2001 - 2002

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    KOIDE Yukio, UCHIJIMA Masato, NAGATA Toshi, OHARA Naoya, AOSHI Taiki

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    Grant amount：\3900000 （ Direct expense: \3900000 ）

    The best vaccine available against tuberculosis (TB), BCG, gives variable protective efficacy. Therefore, there remains an urgent need for an improved vaccine. DNA vaccine is capable of inducing strong cellular immunity involved in the protection against TB. Therefore, DNA vaccine is a candidate to induce more effective protective immunity against TB. We, previously, observed that DNA vaccine expressing a single epitope is more potent in the induction of protective immunity than that encoding whole molecules. In this project, therefore, we tried to identify T-cell epitopes of M. tuberculosis antigens. As we demonstrated that MPB51 antigen is one of major protective antigens of M. tuberculosis. We attempted T-cell epitopes of MPB51 employing overlapping peptide library and computer algorism. Then, we found I-A^b-restricted CD4 T-cell epitopes in amino acid residues 171-190 and 191-210 and an H-2^b-restricted CD8 T-cell in residues 21-40. Furthermore, employing H-2 class I knockout, HLA-A^*0201-transgenic mice, we found an HLA-A^*0201-restricted CD8^+T-cell epitope of MPB51.

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  • 歯周病原細菌における低分子ストレスタンパク質による広範囲調節機構の解析

    Grant number：11771117  1999 - 2000

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    大原 直也

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    Grant amount：\2200000 （ Direct expense: \2200000 ）

    歯周疾患関連細菌であるPorphyromonas gingivalisを用いて偏性嫌気性菌の酸素暴露における適応機構を解明することを目的として、嫌気状態と酸素暴露下における同菌の蛋白質の発現パターンの違いをP.gingivalis381株を用いて検討した。酸素暴露下において発現量の顕著に増加する蛋白質が複数存在することを昨年度報告したが、今年度は昨年度に引続きこれらの蛋白質の同定をおこなった。その結果、ほとんどの蛋白質はすでに報告されているSOD、AhpC、TpX等の分子であった。しかし、分子量約9kDa、等電点約4.7の蛋白質についてその部分アミノ酸配列を決定したところ、これまでに報告されていない分子であることが推定された。その遺伝子から予測される分子量、等電点はそれぞれ9194.89、4.74であった。この蛋白質をPG9とした。ところで、酸素ストレスによって発現が上昇する蛋白質の遺伝子を支配するものにOxyRが知られているが、PG9の遺伝子がOxyRの支配を受けているかを検討した。
    P.gingivalis381株、33277株、およびそのOxyR::Tc株(oxyR欠損株)を嫌気培養後、酸素に暴露し、継時的に菌体を破砕し、RT-PCR法にてPG9のmRNA量の変化を調べた。その結果、OxyR::Tc株においても酸素暴露によりPG9のmRNA量は増加したが、親株に対してmRNA量が増加する時間が遅延することが明らかになった。このことから、PG9はOxyRの支配を部分的に受けていることが推測された。現在PG9の欠損株を作成し、酸素暴露下におけるPG9の役割を解析中である。

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  • マラリアのワクチン開発を目指した,BCGからのSERA抗原発現の試み

    Grant number：10166218  1998

    日本学術振興会  科学研究費助成事業  特定領域研究(A)

    山田 毅, 内藤 真理子, 松本 壮吉, 大原 直也

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    Grant amount：\1500000 （ Direct expense: \1500000 ）

    マラリアワクチン開発で,最も障害となっているのがアジュバントの問題である.動物実験等で,防御効果が確認されている抗原を,実際にヒトに投与するには,安全性と有効性を兼ね備えたアジュバントが必要であるが,未だ十分なものが無い.我々は熱帯医学研究所神原廣二教授との共同研究で,組み換えBCGのシステムを用いて,マウスを用いた赤内型マラリア原虫感染防御に成功し,その防御機構が,細胞性免疫をベースにした防御抗体産生誘導であることを,数年にわたる解析の結果,明らかにし,本年発表した(J.Exp.Med.,1998).さらに,BCGシステムを,ヒトに応用するため,熱帯熱マラリアの防御抗原SERAをα抗原をキャリアーとしてBCGから発現させることを試みた.SERAをコードする合成遺伝子をα抗原遺伝子の様々な場所に挿入し,合計7種類の組み換えBCGを作製した.それらを,試験管内で培養し,分泌抗原中の蛋白質を解析してきたが,現在までの所,十分量のSERA抗原を発現する,組み換えBCG菌は得られていない.この原因は,1;発現させるのにSERAの分子量が大きすぎる,2;SERA抗原の一定部位が分泌に適さない(不溶体を形成する),3;使用コドンの不適合,4;プロモーター活性が低い等の原因が考えられた.現在1,2の原因を解決すべく,SERA遺伝子を分割して,発現させることを試みている.また,α抗原以外のキャリアー蛋白質の検討を行い,抗体産生能の高いMDP1等の抗原とSERAの融合蛋白質を発現させる,プラスミッドを構築している.

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  • A study for non-specific or specific immunochemotherapy by using recombinant BCG

    Grant number：09672056  1997 - 2000

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    MATSUO Takemitsu, NAITO Mariko, OHARA Naoya

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    Grant amount：\3300000 （ Direct expense: \3300000 ）

    Mycobacterium bovis BCG (BCG) secrete different antigenic proteins. The amount and anti-tumor effects depend on BCG substrains. BCG has not only a direct anti-tumor effects but also indirect effects mediated macrophages. In order to study for an anti-cancer immuno-chemotherapy by using recombinant BCG, first we studied expression mechanisms, regulatory factors, and DNA binding proteins. Secondly we examined direct anti-tumor effects. Finally we investigated indirect anti-tumor effects mediated macrophages.
    BCG substrain Tokyo (BCG Tokyo) secrete a large amount of the MPB70 protein, whereas BCG substrain Pasteur secrete little. The MPB70 genes in two substrains showed exactly the same sequence, and regulated transcriptional stage. We confirmed DNA binding proteins by gel shift assay, then extracted a 20 kDa protein, and confirmed a single strand DNA binding protein.
    We prepared culture filtrate (CF) and cell lysate (Ly) by BCG Tokyo, then measured anti-tumor effects. The cell growth was measured by the human squamous cell carcinoma cell line (SCC-25) and human gingival fibroblast cell line (HGF). CF and Ly dose-dependently inhibited the cell growth of SCC-25. The inhibition effect of CF was higher than that of Ly and the anti-tumor effect of CF was also greater.
    For an indirect anti-tumor effects mediating macrophages, we examined the secreted proteins of BCG released to the cytoplasm from the phagosome by BCG infected macrophages. The MPB70 protein was shown only the phagosomal fraction. We suppose the MPB70 protein released to the cytoplasm from the phagosome. Same result was observed for BCG infected SCC-25. Usually, bacteria were phagocyted by macrophage and fragmented into peptides in phagosome. These peptides bound to MHC class II molecules. But it was thought that the proteins released to the cytoplasm are fragmented peptides and bound to MHC class I molecules. According to exam, possibility was suggested to make CTLs activate much more.

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  • 歯周疾患関連菌に新しく発見された挿入配列の病原性への関与

    Grant number：09771508  1997 - 1998

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    大原 直也

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    Grant amount：\1900000 （ Direct expense: \1900000 ）

    我々はActinobacillus(Haemophilus)actinomycetemcomitans(A.a.)FDC Y4株の染色体中に、IS200様の挿入配列が存在することを見出し、ISAa1と名付けた。昨年度は種内と種間におけるISAa1の分布についての検討を行ったが、今年度は主にISAa1の挿入箇所および転移活性についての検討をおこなった。
    (1) ISAa1の挿入箇所について:昨年明らかにしたリボゾーム蛋白質遺伝子クラスター中への挿入以外に新たに6箇所の挿入部位を検討した。そのうち4箇所については既存の遺伝子内にISAa1が挿入された可能性が高い。pyrG(CTP synthatase)、carA(carbamoylphosphate synthetase heavy subunit)、omp34(outer membrane protein 34)およびrrn(ribosomal RNA operon)である。omp34はFc結合性タンパク質と報告されていることから宿主-寄生体関係に影響を与えていることが示唆される。また、rrnは生物にとって必須であるrRNAをコードしていることから、菌の生育に影響を与えている可能性があり、興味深い。
    (2) 転移活性について:以前にISAa1の標的配列を、TTATTと推測した。しかし、上記挿入箇所の塩基配列を検討してみると必ずしもこの配列に従っていない。基本配列がTTTTTであり、そのうち1ないし2塩基が他の塩基と入れ代わることが許容されている可能性が高い。しかし、現時点で実験的根拠はなく、現在このことを証明する実験をおこなっている。なお、TTTTTあるいは類似した配列は同菌のゲノム中には多く存在し、このことが菌株によってはISAa1が多コピー存在する理由であろう。

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  • う蝕の遺伝子治療に関する基礎的研究

    Grant number：09877367  1997 - 1998

    日本学術振興会  科学研究費助成事業  萌芽的研究

    林 善彦, 大原 直也

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    Grant amount：\2200000 （ Direct expense: \2200000 ）

    平成9年度は、E.COliにアルカリフォスファテース(PhoA)遺伝子を導入しその酵素活性を人為的に上昇させ、適切な条件下で培養すると菌体内に針状結晶の生じることを明らかにした。平成10年度は、このシステムをう蝕原性細菌に応用して以下の実験を行った。使用した菌種として、口腔常在性乳酸菌近縁の乳酸菌(Lactococcus lactis)を用いた。
    (1) 乳酸菌の人為的石灰化の可能性
    E.coliより粗精製したPhoAと、グリセロリン酸カルシウムを培地中に添加しL.lactisを培養したところ、乳酸菌の産生する酸によって培地のpHが低下することが明らかとなった。そこで、種々検討した結果、炭水化物を含まない培地を用いることによって、この点を改善することができた。菌体を回収し凍結乾燥後、フーリエ変換赤外分光分析を試みたところ、既知のハイドロキシアパタイトのピークと一致する新たなスペクトルを証明できた。
    (2) 乳酸菌のPhoA遺伝子のクローニング
    乳酸菌においては、いまだPhoAの存在および遺伝子配列に関する報告がない。そこで、E.coliのPhoA遺伝子をプローブとしてサザンハイブリダイゼーションを行ったが、明らかに反応するバンドは検出できなかった。そこで、PhoA活性を有する他の菌種において保存されている領域のアミノ酸配列をもとにプライマーを設計し、PCRを行った。その結果、期待される約140bpの位置にバンドを認めることができた。

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  • 歯周病関連菌リボゾーム画分に存在する免疫活性物質の研究

    Grant number：07771697  1995

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    大原 直也

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    Grant amount：\800000 （ Direct expense: \800000 ）

    歯周疾患関連菌のリボゾーム蛋白質の免疫活性を研究する前段階として、リボゾーム蛋白質をコードしている遺伝子およびその遺伝子から推測されるアミノ酸配列について検討をおこなった。そのために、Porphyromonas gingivalisについてはそのゲノムDNAを4塩基対認識酵素で部分分解後、λファージを用いて遺伝子ライブラリーを作成した。Actinobacillus actinomycetemcomitansについては6塩基対認識酵素で完全分解ゲノムサザン法をおこなった。両者に対するプローブとして、既知のBacillus属あるいはMycobacterium属のリボゾーム蛋白質遺伝子を用いクローニングをおこなった。その結果、A.actinomycetemcomitansのリボゾーム蛋白質遺伝子については興味深い知見が得られた。
    S10オペロン、spcオペロンのクラスター配列が、A.actinomycetemcomitansにおいては他の細菌とは異なっていた。この理由として、この菌ではS10オペロンの下流に存在した挿入配列様構造(ISAal)が原因と考えられる。他のリボゾーム蛋白質遺伝子のオペロンもこのISAalによって、オペロン間の配列が乱されていることが示唆された。
    次にISAalのコピー数について検討した。血清型a,b,cの数株について調べたところ、ISAalのコピー数は血清型によって異なることが示唆された。このことについてはさらにサンプル数を増やして検討する必要がある。以前より血清型bの病原性が強いことがいわれているが、このISAalのコピー数、挿入部位(特にリボゾーム蛋白質遺伝子のオペロン)との相関関係の有無については今後の検討課題である。

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  • 歯周病関連菌のリボゾーム蛋白質の歯周疾患発症における意義

    Grant number：06771672  1994

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    大原 直也

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    Grant amount：\1000000 （ Direct expense: \1000000 ）

    歯周疾患関連菌のリボゾーム蛋白質を研究するにあたり、最初にリボゾーム蛋白質をコードしている遺伝子およびその遺伝子から推測されるアミノ酸配列について検討をおこなった。そのために、Porphyromonas gingivalisについてはそのゲノムDNAを4塩基対認識酵素で部分分解後、λファージを用いて遺伝子ライブラリーを作成した。Actinobacillus actinomycetemcomitansについては6塩基対認識酵素で完全分解ゲノムサザン法をおこなった。両者に対するプローブとして、既知のBacillus属あるいはMycobacterium属のリボゾーム蛋白質遺伝子を用いクローニングをおこなった。細菌のリボゾーム蛋白質遺伝子は一般にほとんどのものがオペロン構造をとっているが、これまでに得られた結果では各オペロン内での構造は、これまでに知られている他の菌のリボゾーム蛋白質遺伝子のオペロン構造と顕著に異なる点は見い出せなかった。
    個々のリボゾーム蛋白質の一次構造は大腸菌のものに高い相同性を示し、両菌に特徴的な配列は今までには見い出さなかった。
    ところが、A.actinomycetemcomitansについてはオペロン間に挿入配列様構造が新しく見い出された。この配列の挿入によりリボゾーム蛋白質遺伝子全体の発現調節に影響を与えていることが考えられる。この挿入配列様構造はA.actinomycetemcomitansでは今までに報告されていないものである。また菌株によりその存在の有無が異なるため、疫学への応用が期待される。

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  • Studies for the Development of Recombinant BCG and for the Structure and Function of Secreting Proteins in Mycobacteria

    Grant number：04670248  1992 - 1994

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for General Scientific Research (C)

    KOBAYASHI Kohmei, OHARA Naoya

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    Grant amount：\2100000 （ Direct expense: \2100000 ）

    The purpose of this study was to develope live recombinant BCG vaccine vehicles into which the genes of antigenic proteins of HIV (for AIDS) or Plasmodium (for malaria) were introduced. DNA containing a B-cell epitope region of HIV-1 p17 gag was fused to a shuttle vector at C-turminal of M.Kansasii alpha-antigen gene. Using this vector, we succeeded to produce the foreign antigen in M.bovis BCG.
    The gene for alpha-antigen was isolated from M.avium detected in patients with AIDS.Serological analysis of recombinant M.avium alpha-antigen (A-alpha) indicated the possibility that A-alpha carries at least six B-cell epitopes (Imfection and Immunity, 1993).
    To establish more effective expression system, we are interested in studying MPB70 gene in M.bovis BCG substrain Tokyo which excretes large amounts of MPB70. M.bovis BCG substrain Pasteur which do not excrete MPB70 was used as a reference. It was shown by hybridization technique that the N- or C-turminals of the MPB70 gene was retained even in BCG Pasteur (Biomedical Letters, 1993). Next we prepared 1.6kb DNA fragment containing promotor and the gene to examine the process of expression and secretion of MPB70. MPB70 was then produced in the transformant. A variety of shorter DNA fragments containing the MPB70 gene and its upstream have been designed.
    To construct the live recombinant BCG vaccine vehicles for malaria, M.bovis BCG was transformed with the hybrid DNA fusing synthetic oligonucleotide based on amino acid sequence of cytotoxic T-lympho cyte (CTL) epitope in the antigenic protein of Plasmodium to MPB64 gene. It was recognized that the foreign antigen was produced in the transformant. However, CTL activities were not induced in mice with the BCG recombinant.

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  • 歯周病発病の分子機構の研究(口腔細菌のストレス蛋白質遺伝子の構造と機能)

    Grant number：03857258  1991

    日本学術振興会  科学研究費助成事業  奨励研究(A)

    大原 直也

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    Grant amount：\900000 （ Direct expense: \900000 ）

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  • 薬剤耐性結核および非結核性抗酸菌治療薬開発を加速する支援技術の開発

    Grant number：22683171 

    国立研究開発法人日本医療研究開発機構 令和4年度 新興・再興感染症に対する革新的医薬品等開発推進研究事業3次公募 

    瀧井猛将, 大原直也, 浅見行弘, 君嶋葵

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  • Research in Dental Sciences I （2022academic year） special  - その他

  • Research in Dental Sciences II （2022academic year） special  - その他

  • Biomaterials （2022academic year） Concentration  - その他

  • Research Projects and Practicals:Infectious Diseases and Microbiology （2022academic year） special  - その他

  • Lecture and Research Projects:Infectious Diseases and Microbiology （2022academic year） special  - その他

  • New development of gene engineering （2022academic year） Third semester  - 木3～4

  • Health and Oral Diseases （2021academic year） Second semester  - 木5～6

  • Immunology （2021academic year） 1st semester  - 月4,月5

  • Exercise in Medical Education （2021academic year） special  - その他

  • Research Projects and Practicals: Microbiology I （2021academic year） special  - その他

  • Lecture and Research Projects: Microbiology I （2021academic year） special  - その他

  • Research Projects and Practicals: Microbiology II （2021academic year） special  - その他

  • Lecture and Research Projects: Microbiology II （2021academic year） special  - その他

  • Research Presentation in Oral Pathology （2021academic year） special  - その他

  • Practice of Microbiology （2021academic year） 1st semester  - 月1～3,木4～6,金5～7

  • Virology （2021academic year） 1st semester  - 金4

  • Infectious diseases （2021academic year） 1st semester  - 月4,月5

  • Microbiology （2021academic year） Fourth semester  - 木4,木5,木6

  • Exercise in Dental Education （2021academic year） special  - その他

  • Research in Dental Sciences I （2021academic year） special  - その他

  • Research in Dental Sciences II （2021academic year） special  - その他

  • Biomaterials （2021academic year） Concentration  - その他

  • Research Projects and Practicals:Infectious Diseases and Microbiology （2021academic year） special  - その他

  • Lecture and Research Projects:Infectious Diseases and Microbiology （2021academic year） special  - その他

  • New development of gene engineering （2021academic year） Third semester  - 木3～4

  • Virology （2020academic year） 1st semester  - 金4

  • Health and Oral Diseases （2020academic year） Second semester  - 木5～6

  • Immunology （2020academic year） 1st semester  - 月2,月3

  • Immunology （2020academic year） 1st semester  - 月4,月5

  • Practice of Oral Microbiology （2020academic year） 1st semester  - 月4～6,木4～6,金4～6

  • Practice of Oral Microbiology （2020academic year） 1st semester  - 月5～7,木5～7,金5～7

  • Research Projects and Practicals: Microbiology I （2020academic year） special  - その他

  • Lecture and Research Projects: Microbiology I （2020academic year） special  - その他

  • Research Projects and Practicals: Microbiology II （2020academic year） special  - その他

  • Lecture and Research Projects: Microbiology II （2020academic year） special  - その他

  • Research Presentation in Oral Pathology （2020academic year） Year-round  - その他

  • Oral Pathology （2020academic year） Year-round  - その他

  • Microbiology （2020academic year） Fourth semester  - 木1,木2,木3

  • Practice of Microbiology （2020academic year） 1st semester  - 月1～3,木4～6,金5～7

  • Virology （2020academic year） 1st semester  - 金4

  • Infectious diseases （2020academic year） 1st semester  - 月4,月5

  • Practice of Microbiology （2020academic year） 1st semester  - 月4～6,木4～6,金4～6

  • Practice of Microbiology （2020academic year） 1st semester  - 月5～7,木5～7,金5～7

  • Microbiology （2020academic year） Fourth semester  - 木1,木2,木3

  • Infectious Diseases （2020academic year） 1st semester  - 月2,月3

  • Research Projects （2020academic year） Year-round  - その他

  • Biomaterials （2020academic year） Concentration  - その他

  • Research Projects and Practicals:Infectious Diseases and Microbiology （2020academic year） special  - その他

  • Lecture and Research Projects:Infectious Diseases and Microbiology （2020academic year） special  - その他

  • New development of gene engineering （2020academic year） Third semester  - 木3,木4

  • Virology （2019academic year） 1st semester  - 金4

  • Health and Oral Diseases （2019academic year） Second semester  - 木5～6

  • Immunology （2019academic year） 1st semester  - 月4,月5

  • Immunology （2019academic year） 1st semester  - 月2,月3

  • Practice of Oral Microbiology （2019academic year） 1st semester  - 月5～7,木5～7,金5～7

  • Practice of Oral Microbiology （2019academic year） 1st semester  - 月4～6,木4～6,金4～6

  • Research Projects and Practicals: Microbiology I （2019academic year） special  - その他

  • Lecture and Research Projects: Microbiology I （2019academic year） special  - その他

  • Research Projects and Practicals: Microbiology II （2019academic year） special  - その他

  • Lecture and Research Projects: Microbiology II （2019academic year） special  - その他

  • Research Presentation in Oral Pathology （2019academic year） Year-round  - その他

  • Oral Pathology （2019academic year） Year-round  - その他

  • Microbiology （2019academic year） Fourth semester  - 木1,木2,木3

  • Practice of Microbiology （2019academic year） 1st semester  - 月1～3,木4～6,金5～7

  • Virology （2019academic year） 1st semester  - 金4

  • Infectious diseases （2019academic year） 1st semester  - 月4,月5

  • Practice of Microbiology （2019academic year） 1st semester  - 月5～7,木5～7,金5～7

  • Practice of Microbiology （2019academic year） 1st semester  - 月4～6,木4～6,金4～6

  • Microbiology （2019academic year） Fourth semester  - 木1,木2,木3

  • Infectious Diseases （2019academic year） 1st semester  - 月2,月3

  • Research Projects （2019academic year） Year-round  - その他

  • Biomaterials （2019academic year） Concentration  - その他

  • Research Projects and Practicals:Infectious Diseases and Microbiology （2019academic year） special  - その他

  • Lecture and Research Projects:Infectious Diseases and Microbiology （2019academic year） special  - その他

  • New development of gene engineering （2019academic year） Third semester  - 木3,木4

  • Virology （2018academic year） 1st semester  - 金4

  • Health and Oral Diseases （2018academic year） Second semester  - 木5～6

  • Immunology （2018academic year） 1st semester  - 月4,月5

  • Immunology （2018academic year） 1st semester  - 月2,月3

  • Practice of Oral Microbiology （2018academic year） 1st semester  - 月5～7,木5～7,金5～7

  • Practice of Oral Microbiology （2018academic year） 1st semester  - 月4～6,木4～6,金4～6

  • Research Projects and Practicals: Microbiology I （2018academic year） special  - その他

  • Lecture and Research Projects: Microbiology I （2018academic year） special  - その他

  • Research Projects and Practicals: Microbiology II （2018academic year） special  - その他

  • Lecture and Research Projects: Microbiology II （2018academic year） special  - その他

  • Research Presentation in Oral Pathology （2018academic year） Year-round  - その他

  • Oral Pathology （2018academic year） Year-round  - その他

  • Microbiology （2018academic year） Fourth semester  - 木1,木2,木3

  • Practice of Microbiology （2018academic year） 1st semester  - 月1～3,木4～6,金5～7

  • Virology （2018academic year） 1st semester  - 金4

  • Infectious diseases （2018academic year） 1st semester  - 月4,月5

  • Practice of Microbiology （2018academic year） 1st semester  - 月5～7,木5～7,金5～7

  • Practice of Microbiology （2018academic year） 1st semester  - 月4～6,木4～6,金4～6

  • Microbiology （2018academic year） Fourth semester  - 木1,木2,木3

  • Infectious Diseases （2018academic year） 1st semester  - 月2,月3

  • Research Projects （2018academic year） Year-round  - その他

  • Biomaterials （2018academic year） Concentration  - その他

  • Research Projects and Practicals:Infectious Diseases and Microbiology （2018academic year） special  - その他

  • Lecture and Research Projects:Infectious Diseases and Microbiology （2018academic year） special  - その他

  • New development of gene engineering （2018academic year） Third semester  - 木3,木4

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Social Activities

  • 結核菌はどのような病原体か

    Role(s)：Lecturer

    琉球大学熱帯生物圏研究センター  琉球大学熱帯生物圏研究センター 市民公開シンポジウム  2019.10.20