研究者詳細 - 本田　知之

論文 - 本田　知之

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Borna disease virus possesses an NF-ĸB inhibitory sequence in the nucleoprotein gene. 査読

Makino A, Fujino K, Parrish NF, Honda T, Tomonaga K

Scientific reports 5 8696 2015年3月

ボルナ病ウイルス感染症の病態研究

本田知之, 朝長啓造

化学療法の領域 31 ( 4 ) 640 - 647 2015年

Neuropathogenesis of persistent infection with Borna disease virus. 査読

Honda T

Uirusu 65 ( 1 ) 145 - 154 2015年

担当区分：筆頭著者,　責任著者記述言語：日本語出版者・発行元：日本ウイルス学会

ボルナ病ウイルス(Borna disease virus: BDV)は，強い神経指向性を持ち，中枢神経系へ持続感染するマイナス鎖RNAウイルスである．自然感染した動物では，致死性脳炎から軽微な神経症状まで，様々な神経症状を呈する．BDV感染による病原性発現の分子メカニズムについては，未だ不明な点が多い．細胞非傷害性であるBDVの病原性は，必ずしもウイルス量に相関せず，感染細胞の質的変化・機能異常によるものと考えられる．これは多くの細胞傷害性ウイルスの病原性がウイルス量と相関するのと大きく異なる．本稿では，BDV感染による病原性発現機構について，私たちが見出した２つの現象を紹介する．グリア細胞は，BDV Pタンパク質発現により，周辺のIGFシグナルの異常を引き起こし，BDV感染病態を誘導する．一部の感染細胞では，BDV mRNAの逆転写と宿主ゲノムへのインテグレーションが起こる．この挿入配列は，BDVタンパク質のバランス変化，BDVを認識するpiRNA産生，周辺遺伝子の発現変化などを引き起こしうる．BDV感染動物では，これらが複雑に絡み合い，様々な症状を呈しているものと考えられる．

DOI： 10.2222/jsv.65.145

その他リンク： https://jlc.jst.go.jp/DN/JLC/20013922106?from=CiNii

ボルナ病ウイルスの神経病原性に関する研究

本田知之

ウイルス 65 ( 1 ) 145 - 154 2015年

記述言語：日本語出版者・発行元：日本ウイルス学会

ボルナ病ウイルス(Borna disease virus: BDV)は，強い神経指向性を持ち，中枢神経系へ持続感染するマイナス鎖RNAウイルスである．自然感染した動物では，致死性脳炎から軽微な神経症状まで，様々な神経症状を呈する．BDV感染による病原性発現の分子メカニズムについては，未だ不明な点が多い．細胞非傷害性であるBDVの病原性は，必ずしもウイルス量に相関せず，感染細胞の質的変化・機能異常によるものと考えられる．これは多くの細胞傷害性ウイルスの病原性がウイルス量と相関するのと大きく異なる．本稿では，BDV感染による病原性発現機構について，私たちが見出した２つの現象を紹介する．グリア細胞は，BDV Pタンパク質発現により，周辺のIGFシグナルの異常を引き起こし，BDV感染病態を誘導する．一部の感染細胞では，BDV mRNAの逆転写と宿主ゲノムへのインテグレーションが起こる．この挿入配列は，BDVタンパク質のバランス変化，BDVを認識するpiRNA産生，周辺遺伝子の発現変化などを引き起こしうる．BDV感染動物では，これらが複雑に絡み合い，様々な症状を呈しているものと考えられる．

DOI： 10.2222/jsv.65.145

その他リンク： https://jlc.jst.go.jp/DN/JLC/20013922106?from=CiNii

Heat stress is a potent stimulus for enhancing rescue efficiency of recombinant Borna disease virus 査読

Shohei Kojima, Tomoyuki Honda, Yusuke Matsumoto, Keizo Tomonaga

MICROBIOLOGY AND IMMUNOLOGY 58 ( 11 ) 636 - 642 2014年11月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Recently developed vector systems based on Borna disease virus (BDV) hold promise as platforms for efficient and stable gene delivery to the central nervous system (CNS). However, because it currently takes several weeks to rescue recombinant BDV (rBDV), an improved rescue procedure would enhance the utility of this system. Heat stress reportedly enhances the rescue efficiency of other recombinant viruses. Here, heat stress was demonstrated to increase the amount of BDV genome in persistently BDV-infected cells without obvious cytotoxicity. Further analyses suggested that the effect of heat stress on BDV infection is not caused by an increase in the activity of BDV polymerase. More cells in which BDV replication occurs were obtained in the initial phase of rBDV rescue by using heat stress than when it was not used. Thus, heat stress is a useful improvement on the published rescue procedure for rBDV. The present findings may accelerate the practical use of BDV vector systems in basic science and the clinic and thus enable broader adoption of this viral vector, which is uniquely suited for gene delivery to the CNS.

DOI： 10.1111/1348-0421.12193

Inhibition of Borna disease virus replication by an endogenous bornavirus-like element in the ground squirrel genome 査読

Kan Fujino, Masayuki Horie, Tomoyuki Honda, Dana K. Merriman, Keizo Tomonaga

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 111 ( 36 ) 13175 - 13180 2014年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATL ACAD SCIENCES

Animal genomes contain endogenous viral sequences, such as endogenous retroviruses and retrotransposons. Recently, we and others discovered that nonretroviral viruses also have been endogenized in many vertebrate genomes. Bornaviruses belong to the Mononegavirales and have left endogenous fragments, called "endogenous bornavirus-like elements" (EBLs), in the genomes of many mammals. The striking features of EBLs are that they contain relatively long ORFs which have high sequence homology to the extant bornavirus proteins. Furthermore, some EBLs derived from bornavirus nucleoprotein (EBLNs) have been shown to be transcribed as mRNA and probably are translated into proteins. These features lead us to speculate that EBLs may function as cellular coopted genes. An EBLN element in the genome of the thirteen-lined ground squirrel (Ictidomys tridecemlineatus), itEBLN, encodes an ORF with 77% amino acid sequence identity to the current bornavirus nucleoprotein. In this study, we cloned itEBLN from the ground squirrel genome and investigated its involvement in Borna disease virus (BDV) replication. Interestingly, itEBLN, but not a human EBLN, colocalized with the viral factory in the nucleus and appeared to affect BDV polymerase activity by being incorporated into the viral ribonucleoprotein. Our data show that, as do certain endogenous retroviruses, itEBLN potentially may inhibit infection by related exogenous viruses in vivo.

DOI： 10.1073/pnas.1407046111

ボルナウイルス

本田知之

別冊日本臨床新領域別症候群シリーズ「神経症候群Ⅰ」 26 637 - 640 2013年12月

Nucleocytoplasmic Shuttling of Viral Proteins in Borna Disease Virus Infection 査読

Tomoyuki Honda, Keizo Tomonaga

VIRUSES-BASEL 5 ( 8 ) 1978 - 1990 2013年8月

担当区分：筆頭著者,　責任著者記述言語：英語出版者・発行元：MDPI AG

Nuclear import and export of viral RNA and proteins are critical to the replication cycle of viruses that replicate in the nucleus. Borna disease virus (BDV) is a nonsegmented, negative-strand RNA virus that belongs to the order Mononegavirales. BDV has several distinguishing features, one of the most striking being the site of its replication. BDV RNA is transcribed and replicated in the nucleus, while most other negative-strand RNA viruses replicate in the cytoplasm. Therefore, the nucleocytoplasmic trafficking of BDV macromolecules plays a key role in virus replication. Growing evidence indicates that several BDV proteins, including the nucleoprotein, phosphoprotein, protein X and large protein, contribute to the nucleocytoplasmic trafficking of BDV ribonucleoprotein (RNP). The directional control of BDV RNP trafficking is likely determined by the ratios of and interactions between the nuclear localization signals and nuclear export signals in the RNP. In this review, we present a comprehensive view of several unique mechanisms that BDV has developed to control its RNP trafficking and discuss the significance of BDV RNP trafficking in the replication cycle of BDV.

DOI： 10.3390/v5081978

Host Molecular Chaperones: Cell Surface Receptors for Viruses. 査読

Honda T, Tomonaga K

Heat Shock Proteins 7 293 - 307 2013年

Pathogenesis of Encephalitis Caused by Persistent Measles Virus Infection. 査読

Honda T, Yoneda M, Sato H, Kai C

Encephalitis 251 - 262 2013年

Evolutionarily Conserved Interaction between the Phosphoproteins and X Proteins of Bornaviruses from Different Vertebrate Species 査読

Kan Fujino, Masayuki Horie, Tomoyuki Honda, Shoko Nakamura, Yusuke Matsumoto, Ivo M. B. Francischetti, Keizo Tomonaga

PLOS ONE 7 ( 12 ) e51161 2012年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Bornavirus, a non-segmented, negative-strand RNA viruses, is currently classified into several genetically distinct genotypes, such as Borna disease virus (BDV) and avian bornaviruses (ABVs). Recent studies revealed that bornavirus genotypes show unique sequence variability in the putative 5' untranslated region (5' UTR) of X/P mRNA, a bicistronic mRNA for the X protein and phosphoprotein (P). In this study, to understand the evolutionary relationship among the bornavirus genotypes, we investigated the functional interaction between the X and P proteins of four bornavirus genotypes, BDV, ABV genotype 4 and 5 and reptile bornavirus (RBV), the putative 5' UTRs of which exhibit variation in the length. Immunofluorescence and immunoprecipitation analyses using mammalian and avian cell lines revealed that the X proteins of bornaviruses conserve the ability to facilitate the export of P from the nucleus to the cytoplasm via interaction with P. Furthermore, we showed that inter-genotypic interactions may occur between X and P among the genotypes, except for X of RBV. In addition, a BDV minireplicon assay demonstrated that the X and P proteins of ABVs, but not RBV, can affect the polymerase activity of BDV. This study demonstrates that bornaviruses may have conserved the fundamental function of a regulatory protein during their evolution, whereas RBV has evolved distinctly from the other bornavirus genotypes.

DOI： 10.1371/journal.pone.0051161

Generation of Human Bronchial Epithelial Cell Lines Expressing Inactive Mutants of GALNT3 査読

Shoko Nakamura, Masayuki Horie, Kan Fujino, Yusuke Matsumoto, Tomoyuki Honda, Keizo Tomonaga

JOURNAL OF VETERINARY MEDICAL SCIENCE 74 ( 11 ) 1493 - 1496 2012年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC VET SCI

As a tool to understand the role of mucins in the infection of respiratory viruses, we established cell lines stably expressing inactive mutants of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which initiates O-glycosylation of mucins. We introduced single amino acid mutation into the regions essential for the enzyme activity of GALNT3 using the expression plasmid of human GALNT3 and transfected the mutant constructs into a human bronchial epithelial cell line, BEAS-2B. We showed that although the mutants of GALNT3 exhibit an authentic localization at the Golgi apparatus, the glycosylation pattern of the expressing cell lines appeared to be different from that of the cells expressing wild-type GALNT3. These results suggested that the established cell lines express inactive forms of GALNT3 and might be useful in investigation of the significance of O-glycosylation of mucins in respiratory virus infections.

DOI： 10.1292/jvms.12-0199

Bornavirus Closely Associates and Segregates with Host Chromosomes to Ensure Persistent Intranuclear Infection 査読

Yusuke Matsumoto, Yohei Hayashi, Hiroko Omori, Tomoyuki Honda, Takuji Daito, Masayuki Horie, Kazuyoshi Ikuta, Kan Fujino, Shoko Nakamura, Urs Schneider, Geoffrey Chase, Tamotsu Yoshimori, Martin Schwemmle, Keizo Tomonaga

CELL HOST & MICROBE 11 ( 5 ) 492 - 503 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：CELL PRESS

Bornaviruses are nonsegmented negative-strand RNA viruses that establish a persistent infection in the nucleus and occasionally integrate a DNA genome copy into the host chromosomal DNA. However, how these viruses achieve intranuclear infection remains unclear. We show that Borna disease virus (BDV), a mammalian bornavirus, closely associates with the cellular chromosome to ensure intranuclear infection. BDV generates viral factories within the nucleus using host chromatin as a scaffold. In addition, the viral ribonucleoprotein (RNP) interacts directly with the host chromosome throughout the cell cycle, using core histones as a docking platform. HMGB1, a host chromatin-remodeling DNA architectural protein, is required to stabilize RNP on chromosomes and for efficient BDV RNA transcription in the nucleus. During metaphase, the association of RNP with mitotic chromosomes allows the viral RNA to segregate into daughter cells and ensure persistent infection. Thus, bornaviruses likely evolved a chromosome-dependent life cycle to achieve stable intranuclear infection.

DOI： 10.1016/j.chom.2012.04.009

Detection of Avian bornavirus 5 RNA in Eclectus roratus with feather picking disorder 査読

Masayuki Horie, Kengo Ueda, Akiko Ueda, Tomoyuki Honda, Keizo Tomonaga

MICROBIOLOGY AND IMMUNOLOGY 56 ( 5 ) 346 - 349 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Avian bornavirus (ABV) was discovered recently in parrots with proventricular dilatation disease (PDD), a fatal neurological disease. Although ABV has been shown to be a causative agent of PDD, its virological characteristics are largely unknown. Here we report the detection of ABV genotype 5 RNA in an Eclectus roratus with feather picking disorder (FPD). Interestingly, although the bird was persistently infected with ABV5 for at least 8 months, it had no clinical signs of PDD. Although it remains unclear whether ABV5 is associated with FPD, these findings raise the importance of epidemiological studies of birds with diseases other than PDD.

DOI： 10.1111/j.1348-0421.2012.00436.x

Morbillivirus receptors and tropism: multiple pathways for infection 査読

Hiroki Sato, Misako Yoneda, Tomoyuki Honda, Chieko Kai

FRONTIERS IN MICROBIOLOGY 3 75 2012年

記述言語：英語出版者・発行元：FRONTIERS RESEARCH FOUNDATION

Morbilliviruses, which include measles virus (MeV), canine distemper virus, and rinderpest virus, are among the most important pathogens in their respective hosts and cause severe syndromes. Morbilliviruses are enveloped viruses with two envelope proteins, one of which is hemagglutinin (H) protein, which plays a role in binding to cellular receptors. During morbillivirus infection, the virus initially targets lymphoid cells and replicates efficiently in the lymph nodes. The principal cellular receptor for morbillivirus is signaling lymphocyte activation molecule (SLAM, also called CD150), which is exclusively expressed on immune cells. This feature reflects the strong lymphoid cell tropism and viral spread in the infected body. Morbillivirus infection, however, affects various tissues in the body, including the lung, kidney, gastrointestinal tract, vascular endothelium, and brain. Thus, other receptors for morbilliviruses in addition to SLAM might exist. Recently, nectin-4 has been identified as a novel epithelial cell receptor for MeV. The expression of nectin-4 is localized to polarized epithelial cells, and this localization supports the notion of cell tropism since MeV also grows well in the epithelial cells of the respiratory tract. Although two major receptors for lymphoid and epithelial cells in natural infection have been identified, morbillivirus can still infect many other types of cells with low infectivity, suggesting the existence of inefficient but ubiquitously expressed receptors. We have identified other molecules that are implicated in morbillivirus infection of SLAM-negative cells by alternative mechanisms. These findings indicate that morbillivirus utilizes multiple pathways for establishment of infection. These studies will advance our understanding of morbillivirus tropism and pathogenesis.

DOI： 10.3389/fmicb.2012.00075

A Novel Borna Disease Virus Vector System That Stably Expresses Foreign Proteins from an Intercistronic Noncoding Region 査読

Takuji Daito, Kan Fujino, Tomoyuki Honda, Yusuke Matsumoto, Yohei Watanabe, Keizo Tomonaga

JOURNAL OF VIROLOGY 85 ( 23 ) 12170 - 12178 2011年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC MICROBIOLOGY

Borna disease virus (BDV), a nonsegmented, negative- strand RNA virus, infects a wide variety of mammalian species and readily establishes a long- lasting, persistent infection in brain cells. Therefore, this virus could be a promising candidate as a novel RNA virus vector enabling stable gene expression in the central nervous system (CNS). Previous studies demonstrated that the 5' untranslated region of the genome is the only site for insertion and expression of a foreign gene. In this study, we established a novel BDV vector in which an additional transcription cassette has been inserted into an intercistronic noncoding region between the viral phosphoprotein (P) and matrix (M) genes. The recombinant BDV (rBDV) carrying green fluorescent protein (GFP) between the P and M genes, rBDV P/ M- GFP, expressed GFP efficiently in cultured cells and rodent brains for a long period of time without attenuation. Furthermore, we generated a nonpropagating rBDV, Delta GLLP/M, which lacks the envelope glycoprotein (G) and a splicing intron within the polymerase gene (L), by the transcomplementation system with either transient or stable expression of the G gene. Interestingly, rBDV Delta GLLP/M established a persistent infection in cultured cells with stable expression of GFP in the absence of the expression of G. Using persistently infected rBDV Delta GLLP/M-infected cells, we determined the amino acid region in the cytoplasmic tail (CT) of BDV G important for the release of infectious rBDV particles and also demonstrated that the CT region may be critical for the generation of pseudotyped rBDV having vesicular stomatitis virus G protein. Our results revealed that the newly established BDV vector constitutes an alternative tool not only for stable expression of foreign genes in the CNS but also for understanding the mechanism of the release of enveloped virions.

DOI： 10.1128/JVI.05554-11

Recombinant vaccines against the mononegaviruses-What we have learned from animal disease controls 査読

Hiroki Sato, Misako Yoneda, Tomoyuki Honda, Chieko Kai

VIRUS RESEARCH 162 ( 1-2 ) 63 - 71 2011年12月

記述言語：英語出版者・発行元：ELSEVIER SCIENCE BV

The mononegaviruses include a number of highly contagious and severe disease-causing viruses of both animals and humans. For the control of these viral diseases, development of vaccines, either with classical methods or with recombinant DNA virus vectors, has been attempted over the years. Recently reverse genetics of mononegaviruses has been developed and used to generate infectious viruses possessing genomes derived from cloned cDNA in order to study the consequent effects of viral gene manipulations on phenotype. This technology allows us to develop novel candidate vaccines. In particular, a variety of different attenuation strategies to produce a range of attenuated mononegavirus vaccines have been studied. In addition, because of their ideal nature as live vaccines, recombinant mononegaviruses expressing foreign proteins have also been produced with the aim of developing multivalent vaccines against more than one pathogen. These recombinant mononegaviruses are currently under evaluation as new viral vectors for vaccination. Reverse genetics could have great potential for the preparation of vaccines against many mononegaviruses. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.virusres.2011.09.038

Upregulation of Insulin-Like Growth Factor Binding Protein 3 in Astrocytes of Transgenic Mice That Express Borna Disease Virus Phosphoprotein 査読

Tomoyuki Honda, Kan Fujino, Daisuke Okuzaki, Naohiro Ohtaki, Yusuke Matsumoto, Masayuki Horie, Takuji Daito, Masayuki Itoh, Keizo Tomonaga

JOURNAL OF VIROLOGY 85 ( 9 ) 4567 - 4571 2011年5月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC MICROBIOLOGY

In a previous study, we demonstrated that transgenic mice that express Borna disease virus (BDV) phosphoprotein (P) in astrocytes show striking neurobehavioral abnormalities resembling those in BDV-infected animals. To understand the molecular disturbances induced by the expression of P in astrocytes, we performed microarray analysis with cultured astroglial cells transiently expressing P. We showed that expression of insulin-like growth factor binding protein 3 mRNA increases not only in P-expressing cultured cells but also in astrocytes from the cerebella of P transgenic mice (P-Tg). Furthermore, we demonstrated that insulin-like growth factor signaling is disturbed in the P-Tg cerebellum, a factor that might be involved in the increased vulnerability of Purkinje cell neurons in the brain.

DOI： 10.1128/JVI.01817-10

Endogenous non-retroviral RNA virus elements in mammalian genomes 査読

Masayuki Horie, Tomoyuki Honda, Yoshiyuki Suzuki, Yuki Kobayashi, Takuji Daito, Tatsuo Oshida, Kazuyoshi Ikuta, Patric Jern, Takashi Gojobori, John M. Coffin, Keizo Tomonaga

NATURE 463 ( 7277 ) 84 - U90 2010年1月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements(1,2). Although many other viruses, including non-retroviral RNA viruses, are known to generate DNA forms of their own genomes during replication(3-5), none has been found as DNA in the germline of animals. Bornaviruses, a genus of non-segmented, negative-sense RNA virus, are unique among RNA viruses in that they establish persistent infection in the cell nucleus(6-8). Here we show that elements homologous to the nucleoprotein (N) gene of bornavirus exist in the genomes of several mammalian species, including humans, non-human primates, rodents and elephants. These sequences have been designated endogenous Borna-like N (EBLN) elements. Some of the primate EBLNs contain an intact open reading frame (ORF) and are expressed as mRNA. Phylogenetic analyses showed that EBLNs seem to have been generated by different insertional events in each specific animal family. Furthermore, the EBLN of a ground squirrel was formed by a recent integration event, whereas those in primates must have been formed more than 40 million years ago. We also show that the N mRNA of a current mammalian bornavirus, Borna disease virus (BDV), can form EBLN-like elements in the genomes of persistently infected cultured cells. Our results provide the first evidence for endogenization of non-retroviral virus-derived elements in mammalian genomes and give novel insights not only into generation of endogenous elements, but also into a role of bornavirus as a source of genetic novelty in its host.

DOI： 10.1038/nature08695

Molecular Chaperone BiP Interacts with Borna Disease Virus Glycoprotein at the Cell Surface 査読

Tomoyuki Honda, Masayuki Horie, Takuji Daito, Kazuyoshi Ikuta, Keizo Tomonaga

JOURNAL OF VIROLOGY 83 ( 23 ) 12622 - 12625 2009年12月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC MICROBIOLOGY

Borna disease virus (BDV) is characterized by highly neurotropic infection. BDV enters its target cells using virus surface glycoprotein (G), but the cellular molecules mediating this process remain to be elucidated. We demonstrate here that the N-terminal product of G, GP1, interacts with the 78-kDa chaperone protein BiP. BiP was found at the surface of BDV-permissive cells, and anti-BiP antibody reduced BDV infection as well as GP1 binding to the cell surface. We also reveal that BiP localizes at the synapse of neurons. These results indicate that BiP may participate in the cell surface association of BDV.

DOI： 10.1128/JVI.01201-09

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