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

ABSTRACT

Shigella infection poses a significant public health challenge in the developing world. However, lack of a widely available mouse model that replicates human shigellosis creates a major bottleneck to better understanding of disease pathogenesis and development of newer drugs and vaccines. BALB/c mice pre-treated with streptomycin and iron (FeCl ₃ ) plus desferrioxamine intraperitoneally followed by oral infection with virulent Shigella flexneri 2a resulted in diarrhea, loss of body weight, bacterial colonization and progressive colitis characterized by disruption of epithelial lining, loss of crypt architecture with goblet cell depletion, increased polymorphonuclear infiltration into the mucosa, submucosal swelling (edema), and raised proinflammatory cytokines and chemokines in the large intestine. To evaluate the usefulness of the model for vaccine efficacy studies, mice were immunized intranasally with a recombinant protein vaccine containing Shigella invasion protein invasion plasmid antigen B (IpaB). Vaccinated mice conferred protection against Shigella , indicating that the model is suitable for testing of vaccine candidates. To protect both Shigella and Salmonella , a chimeric recombinant vaccine (rIpaB–T2544) was developed by fusing IpaB with Salmonella outer membrane protein T2544. Vaccinated mice developed antigen-specific serum IgG and IgA antibodies and a balanced Th1/Th2 response and were protected against oral challenge with Shigella ( S. flexneri 2a , Shigella dysenteriae , and Shigella sonnei ) using our present mouse model and Salmonella ( Salmonella Typhi and Paratyphi) using an iron overload mouse model. We describe here the development of an oral S higella infection model in wild-type mouse. This model was successfully used to demonstrate the immunogenicity and protective efficacy of a candidate protein subunit vaccine against Shigella .

DOI： 10.1128/iai.00346-24

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

BACKGROUND: Cholera cases have increased globally across the Eastern Mediterranean, Africa, Southeast Asia, and parts of Europe since early 2024. This study aims to identify cholera hotspots and understand the spatial distribution of cholera in Kolkata and surrounding regions, a key cholera reservoir. Additionally, we examine sociodemographic factors and aspects related to water, sanitation, and hygiene (WASH). METHODS: Cholera clusters were detected using kernel density estimation and spatial autocorrelation through Global Moran's-I statistics, with local cluster patterns examined using Local Moran's-I statistics. Cholera cases from August 2021 to December 2023, treated at two tertiary care facilities in Kolkata: Infectious Diseases and Beleghata General Hospital and Dr. B C Roy Post Graduate Institute of Paediatric Sciences Hospital were included. Additionally, through a case-control study, 196 culture-confirmed cholera cases and 764 age/sex-matched neighborhood controls were enrolled, to investigate cholera risk factors. FINDINGS: Spatial analysis revealed a concentration of 196 cholera cases in Kolkata and its surrounding regions of Howrah, Hooghly, and North and South 24 Parganas. Hotspot analysis showed significant clustering in several Kolkata wards (31, 33, 56, 46, 57, 58, 59, 61, 66, 71, and 107), particularly in the northern, central, and east Kolkata wetlands areas (Global Moran's I statistic = 0.14, p < 0.001). These clusters had proximity between cases, with a median distance of 187.7 m, and 25.5% of cases as close as 73.9 m apart, suggesting localized transmission. Hotspots were identified with an average distance of 1600 m between them. Local Moran's I analysis found dense "high-high" clusters in these areas (p < 0.01), with a mean Moran's I index of 0.3, (range 0.1-4.6). The case-control study revealed that males were more likely to contract cholera, with an adjusted odds ratio of 2.4 (p < 0.01). There was no significant association found between cholera infection and sociodemographic factors or various WASH practices. INTERPRETATION: The findings emphasize the importance of targeted interventions, especially in identified hotspots, to mitigate cholera transmission. Addressing Socio-economic, and environmental factors especially improvement in WASH practices may further enhance prevention effects. FUNDING: The author KK, received funding from the program of the Japan Initiative for Global Research Network on Infectious Diseases, (grant id: JP23wm0125004), from the Ministry of Education, Culture, Sports, Science and Technology in Japan, and Japan Agency for Medical Research and Development.

DOI： 10.1016/j.lansea.2024.100510

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/19490976.2024.2428425

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

Abstract

Bacterial reverse transcriptase coding gene (RT) is essential for the production of a small satellite DNA‐RNA complex called multicopy single‐stranded DNA (msDNA). In this study, we found a novel retron, retron‐Vmi1 (Vm85) from Vibrio mimicus. The retron is comprised of the msr‐msd region, orf323, and the ret gene, a genetic organization similar to Salmonella's retron‐Sen2 (St85). The protein sequence of the RNA‐directed DNA polymerase (RT‐Vmi1) is highly homologous to the RTs of Vibrio metoecus, Vibrio parahaemolyticus, and Vibrio vulnificus. Phylogenetic and protein sequence similarity analysis of retron‐Vmi1 ORF323 and RT revealed a close relatedness to retron‐Sen2. We found that retron‐Vmi1 was inserted in the dusA gene, similar to the insertion of the retron‐Vpa1 (Vp96) of V. parahaemolyticus AQ3354, suggesting that retrons can be transferred via the tRNA gene. These results are the first convincing evidence that retron is moving across species. The neighboring genes of retron‐Vmi1 shared high homology with the genetic environment of V. parahaemolyticus and V. vulnificus retrons. We also found two junction points within the retron‐Vmi1 and the dusA gene suggesting that retron‐Vmi1 was inserted into this site in a two‐step manner.

DOI： 10.1111/1348-0421.13181

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jiph.2024.102564

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00430-024-00805-z

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Other Link： https://link.springer.com/article/10.1007/s00430-024-00805-z/fulltext.html

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

ABSTRACT

The lipopeptide antibiotic daptomycin exhibits bactericidal activity against Gram-positive bacteria by forming a complex with phosphatidylglycerol (PG) and lipid II in the cell membrane, causing membrane perforation. With the emergence of daptomycin-resistant bacteria, understanding the mechanisms of bacterial resistance to daptomycin has gained great importance. In this study, we aimed to identify the genetic factors contributing to daptomycin resistance in Bacillus subtilis , a model Gram-positive bacterium. Our findings demonstrated that overexpression of ugtP , which encodes diglucosyldiacylglycerol synthase, induces daptomycin resistance in B. subtilis . Specifically, overexpression of ugtP resulted in increased levels of diglucosyldiacylglycerol (Glc ₂ DAG) and decreased levels of acidic phospholipids cardiolipin and PG, as well as the basic phospholipid lysylphosphatidylglycerol. However, ugtP overexpression did not alter the cell surface charge and the susceptibility to the cationic antimicrobial peptide nisin or the cationic surfactant hexadecyltrimethylammonium bromide. Furthermore, by serial passaging in the presence of daptomycin, we obtained daptomycin-resistant mutants carrying ugtP mutations. These mutants showed increased levels of Glc ₂ DAG and a &gt;4-fold increase in the minimum inhibitory concentration of daptomycin. These results suggest that increased Glc ₂ DAG levels, driven by ugtP overexpression, modify the phospholipid composition and confer daptomycin resistance in B. subtilis without altering the cell surface charge of the bacteria.

IMPORTANCE

Daptomycin is one of the last-resort drugs for the treatment of methicillin-resistant Staphylococcus aureus infections, and the emergence of daptomycin-resistant bacteria has become a major concern. Understanding the mechanism of daptomycin resistance is important for establishing clinical countermeasures against daptomycin-resistant bacteria. In the present study, we found that overexpression of ugtP , which encodes diglucosyldiacylglycerol synthase, induces daptomycin resistance in B. subtilis , a model Gram-positive bacteria. The overexpression of UgtP increased diglucosyldiacylglycerol levels, resulting in altered phospholipid composition and daptomycin resistance. These findings are important for establishing clinical strategies against daptomycin-resistant bacteria, including their detection and management.

DOI： 10.1128/jb.00307-24

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jiph.2024.04.013

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Bacteria in the genus Vibrio are ubiquitous in estuarine and coastal waters. Some species (including Vibrio cholerae and Vibrio vulnificus) are known human pathogens causing ailments like cholera, diarrhea, or septicemia. Notably, V. vulnificus can also cause a severe systemic infection (known as vibriosis) in eels raised in aquaculture facilities. Water samples were periodically collected from the estuary of the Asahi River, located in the southern part of Okayama City, Japan. These samples were directly plated onto CHROMagar Vibrio plates, and colonies displaying turquoise-blue coloration were selected. Thereafter, polymerase chain reaction was used to identify V. cholerae and V. vulnificus. A total of 30 V. cholerae strains and 194 V. vulnificus strains were isolated during the warm season when the water temperature (WT) was higher than 20 °C. Concurrently, an increase in coliforms was observed during this period. Notably, V. vulnificus has two genotypes, designated as genotype 1 and genotype 2. Genotype 1 is pathogenic to humans, while genotype 2 is pathogenic to both humans and eels. The loop-mediated isothermal amplification method was developed to rapidly determine genotypes at a low cost. Of the 194 strains isolated, 80 (41.2%) were identified as genotype 1 strains. Among the 41 strains isolated when the WTs were higher than 28 °C, 25 strains (61.0%) belonged to genotype 1. In contrast, of the 32 strains isolated when the WTs were lower than 24 °C, 27 strains (84.4%) belonged to genotype 2. These results suggest that the distribution of the two genotypes was influenced by WT.

DOI： 10.3390/microorganisms12050877

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00203-024-03956-y

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Other Link： https://link.springer.com/article/10.1007/s00203-024-03956-y/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Mary Ann Liebert Inc  

DOI： 10.1089/fpd.2023.0064

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Other Link： https://www.liebertpub.com/doi/pdf/10.1089/fpd.2023.0064

Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science (PLoS)  

Background

The primary aim of this study was to investigate the occurrence, characteristics, and antimicrobial resistance patterns of various Shigella serogroups isolated from patients with acute diarrhea of the Infectious Diseases Hospital in Kolkata from 2011–2019.

Principal findings

During the study period, Shigella isolates were tested for their serogroups, antibiotic resistance pattern and virulence gene profiles. A total of 5.8% of Shigella spp. were isolated, among which S. flexneri (76.1%) was the highest, followed by S. sonnei (18.7%), S. boydii (3.4%), and S. dysenteriae (1.8%). Antimicrobial resistance against nalidixic acid was higher in almost all the Shigella isolates, while the resistance to β-lactamases, fluoroquinolones, tetracycline, and chloramphenicol diverged. The occurrence of multidrug resistance was found to be linked with various genes encoding drug-resistance, multiple mutations in the topoisomerase genes, and mobile genetic elements. All the isolates were positive for the invasion plasmid antigen H gene (ipaH). Dendrogram analysis of the plasmid and pulsed-field electrophoresis (PFGE) profiles revealed 70–80% clonal similarity among each Shigella serotype.

Conclusion

This comprehensive long-term surveillance report highlights the clonal diversity of clinical Shigella strains circulating in Kolkata, India, and shows alarming resistance trends towards recommended antibiotics. The elucidation of this study’s outcome is helpful not only in identifying emerging antimicrobial resistance patterns of Shigella spp. but also in developing treatment guidelines appropriate for this region.

DOI： 10.1371/journal.pntd.0011964

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

DOI： 10.3389/fmicb.2024.1370093

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Development of safe, highly effective and affordable enteric fever vaccines is a global health priority. Live, oral typhoid vaccines induce strong mucosal immunity and long-term protection, but safety remains a concern. In contrast, efficacy wears off rapidly for injectable, polysaccharide-based vaccines, which elicit poor mucosal response. We previously reported Salmonella Typhi outer membrane protein, T2544 as a potential candidate for bivalent (S. Typhi and S. Paratyphi A) vaccine development. Here, we show that intranasal immunization with a subunit vaccine (chimera of T2544 and cholera toxin B subunit) induced strong systemic and intestinal mucosal immunity and protection from S. Typhi challenge in a mouse model. CTB-T2544 augmented gut-homing receptor expression on lymphocytes that produced Th1 and Th17 cytokines, secretory IgA in stool that inhibited bacterial motility and epithelial attachment, antibody recall response and affinity maturation with increased number of follicular helper T cells and CD4+ central and effector memory cells.

DOI： 10.1038/s41541-024-00812-4

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Other Link： https://www.nature.com/articles/s41541-024-00812-4

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

BACKGROUND: South Asia remains home to foodborne diseases caused by Vibrio species. We aimed to compile and update information on the epidemiology of vibriosis in South Asia. METHODS: For this systematic review and meta-analysis, we searched PubMed, Web of Science, EMBASE, and Google Scholar for studies related to vibriosis in South Asia published up to May 2023. A random-effects meta-analysis was used to estimate the pooled isolation rate of non-cholera-causing Vibrio species. RESULTS: In total 38 studies were included. Seven of these were case reports and 22 were included in the meta-analysis. Reported vibriosis cases were caused by non-O1/non-O139 V. cholerae, V. parahaemolyticus, V. fluvialis, and V. vulnificus. The overall pooled isolation rate was 4.0% (95% CI: 3.0-5.0%) in patients with diarrhea. Heterogeneity was high (I2= 98.0%). The isolation rate of non-O1/non-O139 V. cholerae, V. parahaemolyticus, V. fluvialis were 9.0 (95% CI: 7.0-10.0%), 1.0 (95% CI: 1.0-2.0%), and 2.0 (95% CI: 1.0-3.0%), respectively. Regarding V. parahaemolyticus, O3:K6 was the most frequently isolated serotype. Cases peaked during summer. Several studies reported antibiotic-resistant strains and those harboring extended-spectrum beta-lactamases genes. CONCLUSIONS: This study demonstrates a high burden of infections caused by non-cholera-causing Vibrio species in South Asia.

DOI： 10.1016/j.ijid.2024.01.022

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Worldwide, noroviruses are the leading cause of acute gastroenteritis (AGE) in people of all age groups. In India, norovirus rates between 1.4 to 44.4% have been reported. Only a very few complete norovirus genome sequences from India have been reported.

Objective

To perform full genome sequencing of noroviruses circulating in India during 2017–2021, identify circulating genotypes, assess evolution including detection of recombination events.

Methodology

Forty-five archived norovirus-positive samples collected between October 2017 to July 2021 from patients with AGE from two hospitals in Kolkata, India were processed for full genome sequencing. Phylogenetic analysis, recombination breakpoint analysis and comprehensive mutation analysis were also performed.

Results

Full genome analysis of norovirus sequences revealed that strains belonging to genogroup (G)I were genotyped as GI.3[P13]. Among the different norovirus capsid-polymerase combinations, GII.3[P16], GII.4 Sydney[P16], GII.4 Sydney[P31], GII.13[P16], GII.16[P16] and GII.17 were identified. Phylogenetic analysis confirmed phylogenetic relatedness with previously reported norovirus strains and all viruses were analyzed by Simplot. GII[P16] viruses with multiple residue mutations within the non-structural region were detected among circulating GII.4 and GII.3 strains. Comprehensive mutation analysis and selection pressure analysis of GII[P16] viruses showed positive as well as negative selection sites. A GII.17 strain (NICED-BCH-11889) had an untypeable polymerase type, closely related to GII[P38].

Conclusion

This study highlights the circulation of diverse norovirus strains in eastern India. These findings are important for understanding norovirus epidemiology in India and may have implications for future vaccine development.

DOI： 10.1186/s13099-023-00594-5

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Other Link： https://link.springer.com/article/10.1186/s13099-023-00594-5/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Human Salmonella infections pose significant public health challenges globally, primarily due to low diagnostic yield of systemic infections, emerging and expanding antibiotic resistance of both the typhoidal and non-typhoidal Salmonella strains and the development of asymptomatic carrier state that functions as a reservoir of infection in the community. The limited long-term efficacy of the currently licensed typhoid vaccines, especially in smaller children and non-availability of vaccines against other Salmonella serovars necessitate active research towards developing a multivalent vaccine with wider coverage of protection against pathogenic Salmonella serovars. We had earlier reported immunogenicity and protective efficacy of a subunit vaccine containing a recombinant outer membrane protein (T2544) of Salmonella Typhi in a mouse model. This was achieved through the robust induction of serum IgG, mucosal secretory IgA and Salmonella-specific cytotoxic T cells as well as memory B and T cell response. Here, we report the development of a glycoconjugate vaccine, containing high molecular weight complexes of Salmonella Typhimurium O-specific polysaccharide (OSP) and recombinant T2544 that conferred simultaneous protection against S. Typhi, S. Paratyphi, S. Typhimurium and cross-protection against S. enteritidis in mice. Our findings corroborate with the published studies that suggested the potential of Salmonella OSP as a vaccine antigen. The role of serum antibodies in vaccine-mediated protection is suggested by rapid seroconversion with high titers of serum IgG and IgA, persistently elevated titers after primary immunization along with a strong antibody recall response with higher avidity serum IgG against both OSP and T2544 and significantly raised SBA titers of both primary and secondary antibodies against different Salmonella serovars. Elevated intestinal secretory IgA and bacterial motility inhibition by the secretory antibodies supported their role as well in vaccine-induced protection. Finally, robust induction of T effector memory response indicates long term efficacy of the candidate vaccine. The above findings coupled with protection of vaccinated animals against multiple clinical isolates confirm the suitability of OSP-rT2544 as a broad-spectrum candidate subunit vaccine against human infection due to typhoidal and non-typhoidal Salmonella serovars.

DOI： 10.3389/fimmu.2023.1304170

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：The Society for Antibacterial and Antifungal Agents, Japan  

DOI： 10.4265/jmc.29.2_55

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

BACKGROUND: Ebola virus disease (Ebola) is highly pathogenic, transmissible, and often deadly, with debilitating consequences. Superspreading within a cluster is also possible. In this study, we aim to document Ebola basic reproduction number (R0): the average number of new cases associated with an Ebola case in a completely susceptible population. METHODS: We undertook a systematic review and meta-analysis. We searched PubMed, EMBASE, and Web of Science for studies published between 1976 and February 27, 2023. We also manually searched the reference lists of the reviewed studies to identify additional studies. We included studies that reported R0 during Ebola outbreaks in Africa. We excluded studies that reported only the effective reproduction number (Rt). Abstracting data from included studies was performed using a pilot-tested standard form. Two investigators reviewed the studies, extracted the data, and assessed quality. The pooled R0 was determined by a random-effects meta-analysis. R0 was stratified by country. We also estimated the theoretically required immunization coverage to reach herd-immunity using the formula of (1-1/R0) × 100 %. RESULTS: The search yielded 2042 studies. We included 53 studies from six African countries in the systematic review providing 97 Ebola mean R0 estimates. 27 (with 46 data points) studies were included in the meta-analysis. The overall pooled mean Ebola R0 was 1.95 (95 % CI 1.74-2.15), with high heterogeneity (I2 = 99.99 %; τ2 = 0.38; and p < 0.001) and evidence of small-study effects (Egger's statistics: Z = 4.67; p < 0.001). Mean Ebola R0 values ranged from 1.2 to 10.0 in Nigeria, 1.1 to 7 in Guinea, 1.14 to 8.33 in Sierra Leone, 1.13 to 5 in Liberia, 1.2 to 5.2 in DR Congo, 1.34 to 2.7 in Uganda, and from 1.40 to 2.55 for all West African countries combined. Pooled mean Ebola R0 was 9.38 (95 % CI 4.16-14.59) in Nigeria, 3.31 (95 % CI 2.30-4.32) in DR Congo, 2.0 (95 % CI 1.25-2.76) in Uganda, 1.83 (95 % CI 1.61-2.05) in Liberia, 1.73 (95 % CI 1.47-2.0) in Sierra Leonne, and 1.44 (95 % CI 1.29-1.60) in Guinea. In theory, 50 % of the population needs to be vaccinated to achieve herd immunity, assuming that Ebola vaccine would be 100 % effective. CONCLUSIONS: Ebola R0 varies widely across countries. Ebola has a much wider R0 range than is often claimed (1.3-2.0). It is possible for an Ebola index case to infect more than two susceptible individuals.

DOI： 10.1016/j.tmaid.2023.102685

PubMed

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

ABSTRACT

We isolated a Vibrio fluvialis strain (IDH5335) from a stool sample collected from a patient with diarrhea. In this announcement, we report the complete genomic sequence of this organism, which was obtained by combining Illumina and Oxford Nanopore sequencing data.

DOI： 10.1128/mra.00707-23

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

DOI： 10.1016/j.imlet.2023.09.009

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

Strain KK2020170T, a Gram-stain negative, yellow colony-forming bacterium, was isolated from surface seawater sampled in Kojima Bay, Okayama, Japan. Phylogenetic analysis based on the 16S rRNA gene revealed that strain KK2020170T belongs to the genus Flavobacterium, with Flavobacterium haoranii LQY-7T (98.1% similarity) being its closest relative, followed by Flavobacterium sediminis MEBiC07310T (96.9%) and Flavobacterium urocaniciphilum YIT 12746T (96.0%). Whole-genome shotgun sequencing showed that strain KK2020170T, when paralleled with F. haoranii LQY-7 T, had 81.3% average nucleotide identity, and 24.6% in silico DNA-DNA hybridization values, respectively. The DNA G + C content of strain KK2020170T was 31.1 mol%. The most abundant fatty acids (> 10%) of strain KK2020170T were iso-C15: 0, iso-C17: 0 3-OH and iso-C15: 1 G. The dominant respiratory quinone of the strain was menaquinone MK-6. Based on the phylogenetic and phenotypic analysis results, we propose that strain KK2020170T represents a novel species, for which the name Flavobacterium okayamense sp. nov. has been proposed. The type strain is KK2020170T (= ATCC TSD-280 T = NBRC 115344 T).

DOI： 10.1007/s00203-023-03682-x

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：Mary Ann Liebert Inc  

DOI： 10.1089/jmf.2022.k.0112

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Other Link： https://www.liebertpub.com/doi/pdf/10.1089/jmf.2022.K.0112

Publishing type：Research paper (scientific journal)   Publisher：Korean Society for Parasitology  

Schistosomiasis causes significant morbidity and mortality worldwide. This study aimed to assess the effect of schistosomula lung antigen preparation (SLAP) and soluble egg antigen (SEA) on a murine schistosomiasis mansoni model. Ninety laboratory-bred male Swiss albino mice were divided into 6 groups. Two doses of the vaccine were given at 2-week intervals. All mice were subcutaneously infected with 80±10 Schistosoma mansoni cercariae 2 weeks after the last vaccination dose. They were sacrificed 7 weeks post-infection. Parasitological and histopathological studies were conducted to assess the effect of inoculated antigens (single or combined). The results showed that the combination of SLAP and SEA (combination group) led to a significant reduction in worm burden (65.56%), and liver and intestine egg count (59% and 60.59%, respectively). The oogram pattern revealed a reduction in immature and mature eggs (15±0.4 and 10±0.8, respectively) and an increased number of dead eggs in the combination group (P&lt;0.001). In terms of histopathological changes, the combination group showed notably small compact fibrocellular egg granuloma and moderate fibrosis in the liver. A high percentage of destroyed ova was observed in the intestine of the combination group. This study demonstrates for the first time the prophylactic effect of combined SLAP and SEA vaccine. The vaccine induced a significant reduction in the parasitological and pathological impacts of schistosomiasis mansoni in hepatic and intestinal tissues, making it a promising vaccine candidate for controlling schistosomiasis.

DOI： 10.3347/phd.22154

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Publishing type：Research paper (scientific journal)   Publisher：Korean Society for Parasitology  

Despite the recent progress in public health measures, malaria remains a troublesome disease that needs to be eradicated. It is essential to develop new antimalarial medications that are reliable and secure. This report evaluated the pharmacokinetics and antimalarial activity of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the rodent malaria parasite Plasmodium berghei in vivo. After a single oral dose (75 mg /kg) of N-89, its pharmacokinetic parameters were measured, and t&lt;sub&gt;1/2&lt;/sub&gt; was 0.97 h, T&lt;sub&gt;max&lt;/sub&gt; was 0.75 h, and bioavailability was 7.01%. A plasma concentration of 8.1 ng/ml of N-89 was maintained for 8 h but could not be detected at 10 h. The dose inhibiting 50% of parasite growth (ED&lt;sub&gt;50&lt;/sub&gt;) and ED&lt;sub&gt;90&lt;/sub&gt; values of oral N-89 obtained following a 4-day suppressive test were 20 and 40 mg/kg, respectively. Based on the plasma concentration of N-89, we evaluated the antimalarial activity and cure effects of oral N-89 at a dose of 75 mg/kg 3 times daily for 3 consecutive days in mice harboring more than 0.5% parasitemia. In all the N-89- treated groups, the parasites were eliminated on day 5 post-treatment, and all mice recovered without a parasite recurrence for 30 days. Additionally, administering oral N-89 at a low dose of 50 mg/kg was sufficient to cure mice from day 6 without parasite recurrence. This work was the first to investigate the pharmacokinetic characteristics and antimalarial activity of N-89 as an oral drug. In the future, the following steps should be focused on developing N-89 for malaria treatments; its administration schedule and metabolic pathways should be investigated.

DOI： 10.3347/phd.23044

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

DOI： 10.1016/j.envres.2023.115374

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

DOI： 10.1016/j.parint.2022.102720

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

We have previously reported 1,2,6,7-tetraoxaspiro [7.11]nonadecane (N-89) as a promising antimalarial compound. In this study, we evaluated the effect of transdermal therapy (tdt) of N-89 in combination (tdct) with other antimalarials as an application for children. We prepared ointment formulas containing N-89 plus another antimalarial drug, specifically, mefloquine, pyrimethamine, or chloroquine. In a 4-day suppressive test, the ED50 values for N-89 alone or combined with either mefloquine, pyrimethamine, or chloroquine were 18, 3, 0.1, and 3 mg/kg, respectively. Interaction assays revealed that N-89 combination therapy showed a synergistic effect with mefloquine and pyrimethamine, but chloroquine provoked an antagonistic effect. Antimalarial activity and cure effect were compared for single-drug application and combination therapy. Low doses of tdct N-89 (35 mg/kg) combined with mefloquine (4 mg/kg) or pyrimethamine (1 mg/kg) gave an antimalarial effect but not a cure effect. In contrast, with high doses of N-89 (60 mg/kg) combined with mefloquine (8 mg/kg) or pyrimethamine (1 mg/kg), parasites disappeared on day 4 of treatment, and mice were completely cured without any parasite recurrence. Our results indicated that transdermal N-89 with mefloquine and pyrimethamine provides a promising antimalarial form for application to children.

DOI： 10.3390/pathogens12030398

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.tmaid.2023.102554

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.2147/ijn.s401876

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Publishing type：Research paper (scientific journal)   Publisher：Korean Society for Parasitology  

The discovery of new antimalarial drugs can be developed using asynchronized &lt;i&gt;Plasmodium berghei&lt;/i&gt; malaria parasites in vivo in mice. Studies on a particular stage are also required to assess the effectiveness and mode of action of drugs. In this report, we used endoperoxide 6-(1,2,6,7-tetraoxaspiro [7.11] nonadec-4-yl) hexan-1-ol (N-251) as a model antimalarial compound on &lt;i&gt;P. chabaudi&lt;/i&gt; parasites. We examined the antimalarial effect of N-251 against ring-stage- and trophozoite-stage-rich &lt;i&gt;P. chabaudi&lt;/i&gt; parasites and asynchronized &lt;i&gt;P. berghei&lt;/i&gt; parasites using the 4-day suppressive test. The ED&lt;sub&gt;50&lt;/sub&gt; values were 27, 22, and 22 mg/kg, respectively, and the antimalarial activity of N-251 was verified in both rodent malaria parasites. To assess the stage-specific effect of N-251 in vivo, we evaluated the change of parasitemia and distribution of parasite stages using ring-stage- and trophozoite-stage-rich &lt;i&gt;P. chabaudi&lt;/i&gt; parasites with one-day drug administration for one life cycle. We discovered that the parasitemias decreased after 13 and 9 hours post-treatment in the ring-stage- and trophozoite-stage-rich groups, respectively. Additionally, in the ring-stage-rich N-251 treated group, the ring-stage parasites hindered trophozoite parasite development. For the trophozoite-stage-rich N-251 treated group, the distribution of the trophozoite stage was maintained without a change in parasitemia until 9 hours. Because of these findings, it can be concluded that N-251 suppressed the trophozoite stage but not the ring stage. We report for the first time that N-251 specifically suppresses the trophozoite stage using &lt;i&gt;P. chabaudi&lt;/i&gt; in mice. The results show that &lt;i&gt;P. chabaudi&lt;/i&gt; is a reliable model for the characterization of stage-specific antimalarial effects.

DOI： 10.3347/phd.22119

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Publishing type：Research paper (scientific journal)   Publisher：Future Medicine Ltd  

Aim: To characterize extensively drug-resistant Pseudomonas aeruginosa from a patient with diarrhea. Materials &amp; methods: Antimicrobial susceptibility was tested by the disk diffusion method. The P. aeruginosa genome was sequenced to identify virulence, antibiotic resistance and prophages encoding genes. Results: P. aeruginosa had a wide spectrum of resistance to antibiotics. Genomic analysis of P. aeruginosa revealed 76 genes associated with antimicrobial resistance, xenobiotic degradation and the type three secretion system. Conclusion: This is the first report on diarrhea associated with P. aeruginosa. Since no other organism was identified, the authors assume that the patient had dysbiosis due to antibiotic exposure, leading to antibiotic-associated diarrhea. The in vivo toxicity expressed by the pathogen may be associated with T3SS.

DOI： 10.2217/fmb-2022-0140

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Aims

A rapid rise in resistance to conventional antibiotics for Shigella spp. has created a problem in treating shigellosis. Hence, there is an urgent need for new and non-conventional anti-bacterial agents. The aim of this study is to show how Asiatic acid, a plant-derived compound, inhibits the intracellular growth of Shigella flexneri.

Methods and results

Shigella flexneri sensitive and resistant strains were used for checking antimicrobial activity of Asiatic acid by gentamicin protection assay. Asiatic acid inhibited the intracellular growth of all strains. Gene expression analysis showed antimicrobial peptide (AMP) up-regulation by Asiatic acid in intestinal cells. Further western blot analysis showed that ERK, p38, and JNK are activated by Asiatic acid. ELISA was performed to check IL-8, IL-6, and cathelicidin secretion. The antibacterial effect of Asiatic acid was further verified in an in vivo mouse model.

Conclusions

The reason behind the antibacterial activities of Asiatic acid is probably over-expression of antimicrobial peptide genes. Besides, direct antimicrobial activities, antimicrobial peptides also carry immunomodulatory activities. Here, Asiatic acid increased IL-6 and IL-8 secretion to induce inflammation. Overall, Asiatic acid up-regulates antimicrobial peptide gene expression and inhibits intracellular S. flexneri growth. Moreover, Asiatic acid reduced bacterial growth and recovered intestinal tissue damages in in vivo mice model.

DOI： 10.1093/jambio/lxac076

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s11274-022-03436-9

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Other Link： https://link.springer.com/article/10.1007/s11274-022-03436-9/fulltext.html

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

DOI： 10.1111/jam.15794

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jam.15794

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Antimicrobial resistance (AMR) in bacteria is an important global health problem affecting humans, animals, and the environment. AMR is considered as one of the major components in the “global one health”. Misuse/overuse of antibiotics in any one of the segments can impact the integrity of the others. In the presence of antibiotic selective pressure, bacteria tend to develop several defense mechanisms, which include structural changes of the bacterial outer membrane, enzymatic processes, gene upregulation, mutations, adaptive resistance, and biofilm formation. Several components of mobile genetic elements (MGEs) play an important role in the dissemination of AMR. Each one of these components has a specific function that lasts long, irrespective of any antibiotic pressure. Integrative and conjugative elements (ICEs), insertion sequence elements (ISs), and transposons carry the antimicrobial resistance genes (ARGs) on different genetic backbones. Successful transfer of ARGs depends on the class of plasmids, regulons, ISs proximity, and type of recombination systems. Additionally, phage-bacterial networks play a major role in the transmission of ARGs, especially in bacteria from the environment and foods of animal origin. Several other functional attributes of bacteria also get successfully modified to acquire ARGs. These include efflux pumps, toxin-antitoxin systems, regulatory small RNAs, guanosine pentaphosphate signaling, quorum sensing, two-component system, and clustered regularly interspaced short palindromic repeats (CRISPR) systems. The metabolic and virulence state of bacteria is also associated with a range of genetic and phenotypic resistance mechanisms. In spite of the availability of a considerable information on AMR, the network associations between selection pressures and several of the components mentioned above are poorly understood. Understanding how a pathogen resists and regulates the ARGs in response to antimicrobials can help in controlling the development of resistance. Here, we provide an overview of the importance of genetic network and regulation of AMR in bacterial pathogens.

DOI： 10.3389/fcimb.2022.952491

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

We examined the stools of 23 patients in Kolkata, who were diagnosed as cholera patients because Vibrio cholerae O1 was detected from their stools by culturing methods, and further explored by metagenomic sequencing analysis. Subsequently, the presence of the gene encoding A subunit of cholera toxin (ctxA) and the cholera toxin (CT) level in these stool samples were examined. ctxA was examined by both metagenomic sequencing analysis and polymerase chain reaction. In these examinations, two samples did not show positive in any of these tests. The metagenomic analysis showed that the genes for Streptococcus pneumoniae and Salmonella enterica were present in the stools of these two patients, respectively. Therefore, these two patients were not considered to have diarrhea due to V. cholerae infection. From these results, we predicted that some Kolkata residents harbor a small number of V. cholerae in their intestines as a form of subclinical infection with V. cholerae. Next, we analyzed the stool samples of 22 diarrhea patients from which V. cholerae was not isolated. The results showed that 3 of the patients seemed to have subclinical infection of V. cholerae based on the amount of the genes. These results indicated that subclinical infections with V. cholerae O1 occur in Kolkata.

DOI： 10.1038/s41598-022-24167-9

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Other Link： https://www.nature.com/articles/s41598-022-24167-9

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

Shigella remains one of the most common causes of diarrhoea in South Asia. Current estimates of the prevalence of Shigella are critical for guiding control measures. We estimated the prevalence of Shigella species and serogroups in South Asia.

Methods

We performed a systematic review using PubMed, EMBASE, Google Scholar and Web of Science for peer-reviewed studies published between 2000 and 19 June 2022. We also manually searched the reference lists of the reviewed studies to identify additional studies. We included studies that detected the presence of Shigella in stool by culture or polymerase chain reaction (PCR). Studies associated with outbreaks were excluded. Two investigators independently reviewed the studies, extracted the data and performed quality assessment. A random-effects meta-analysis was performed to determine the pooled prevalence of Shigella.

Results

Our search yielded 5707 studies, of which 91 studies from five South Asian countries were included in the systematic review, 79 in the meta-analysis of Shigella prevalence and 63 in the meta-analysis of Shigella serogroups prevalence. The pooled prevalence of Shigella was 7% [95% confidence interval (CI): 6–7%], with heterogeneity (I2 = 98.7; P &amp;lt; 0.01). The prevalence of Shigella was higher in children aged &amp;lt;5 years (10%; 95% CI: 8–11%), in rural areas (12%; 95% CI: 10–14%) and in studies using PCR (15%; 95% CI: 11–19%).

Shigella flexneri (58%) was the most abundant serogroup, followed by Shigella sonnei (19%), Shigella boydii (10%) and Shigella dysenteriae (9%). Shigella flexneri 2a was the most frequently isolated serotype (36%), followed by serotype 3a (12%), serotype 6 (12%) and serotype 1b (6%). The prevalence of non-typeable Shigella was 10.0%.

Conclusions

Although the prevalence of Shigella in South Asia remains generally high, it varies by age group and geographical area, with data lacking in some countries. Effective Shigella vaccines would be advantageous for both endemic communities and travellers.

DOI： 10.1093/jtm/taac132

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Other Link： https://academic.oup.com/jtm/article-pdf/30/1/taac132/49254194/taac132.pdf

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

India is an attractive destination for travelers. Unfortunately, numerous reports exist on traveler’s diarrhea (TD) and fecal colonization with extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) among international travelers visiting India. Here, we systematically reviewed studies published on the acquisition of ESBL-EC and TD attack rates among international visitors to India.

Methods

Design: Systematic review and meta-analysis.

A systematic search was performed using Google Scholar, PubMed, EMBASE, Web of Science, and gray literature from 2000 to December 2021, for studies containing data for ESBL-EC acquisition or TD experience related to a trip to India. Random effects models were used to compute the prevalence of ESBL-EC acquisition and TD attack.

Results

The literature search yielded a total of 5023 records. Of these, 31 met our inclusion criteria for systematic review and only 17 could be meta-analyzed (9 for TD, and 8 for ESBL-EC). The overall pooled attack rate of TD was 39% (95% confidence interval, CI: 25–53%). In studies where travelers' memory was used to diagnose TD, the pooled attack rate of TD was slightly higher (42%, 95% CI: 21–64%) compared to those where TD was objectively documented (33%, 95% CI: 17–49%). There were significant risks to be colonized with ESBL-EC among the travelers who experienced TD. The pooled rate of ESBL-EC colonization was 72% (CI: 67–78%). Most ESBL-EC produced CTX-M-15 enzyme. Furthermore, most of the travelers who acquired ESBL-EC were from highly industrialized countries recruited from travel clinics: Canada (n = 80), Germany (n = 69), Netherlands (n = 20), Sweden (n = 18), Japan (n = 10), Finland (n = 8), USA (n = 7), Spain (n = 5), and Denmark (n = 3).

Conclusions

TD pooled attack rate and ESBL-EC acquisition among international travelers visiting India were high in this study. However, we cannot make generalizations based upon this TD pooled attack rate for the current situation, due to a lack of current data. Our study highlights that travelers should be advised on TD to ensure that they do not disregard the risk of contracting TD and be better prepared as a result. It also illustrates the importance of international travel in acquiring antibiotic-resistant Escherichia coli.

DOI： 10.1186/s40794-022-00179-1

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Other Link： https://link.springer.com/article/10.1186/s40794-022-00179-1/fulltext.html

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s42770-022-00788-0

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Other Link： https://link.springer.com/article/10.1007/s42770-022-00788-0/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Rotavirus (RV) is the leading cause of acute gastroenteritis and watery diarrhea in children under 5 years accounting for high morbidity and mortality in countries with poor socioeconomic status. Although vaccination against RV has been implemented in more than 100 countries, the efficacy of vaccine has been challenged in low-income settings. The lack of any FDA-approved drug against RV is an additional concern regarding the treatment associated with rotavirus-induced infantile death. With the purpose for the discovery of anti-RV therapeutics, we assessed anti-rotaviral potential of quercetin, a well-characterized antioxidant flavonoid. In vitro study revealed that quercetin treatment resulted in diminished production of RV-SA11 (simian strain) viral particles in a concentration-dependent manner as estimated by the plaque assay. Consistent with this result, Western blot analysis also revealed reduced synthesis of viral protein in quercetin-treated RV-SA11-infected MA104 cells compared to vehicle (DMSO) treated controls. Not surprisingly, infection of other RV strains A5-13 (bovine strain) and Wa (Human strain) was also found to be abridged in the presence of quercetin compared to DMSO. The IC₅₀ of quercetin against three RV strains ranges between 2.79 and 4.36 Mm, and S.I. index is greater than 45. Concurrent to the in vitro results, in vivo study in mice model also demonstrated reduced expression of viral proteins and viral titer in the small intestine of quercetin-treated infected mice compared to vehicle-treated infected mice. Furthermore, the result suggested anti-rotaviral activity of quercetin to be interferon-independent. Mechanistic study revealed that the antiviral action of quercetin is co-related with the inhibition of RV-induced early activation of NF-κB pathway. Overall, this study delineates the strong anti-RV potential of quercetin and also proposes it as future therapeutics against rotaviral diarrhea.

DOI： 10.3389/fmicb.2022.951716

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Canadian Science Publishing  

The degradation of polymeric chitin by chitinase liberates soluble N-acetyl glucosamine oligosaccharides (GlcNAc_n≥2), a source of nutrition that can also induce a state of natural genetic competence in Vibrio parahaemolyticus. This analysis revealed that among seven predicted chitinases, the synergistic action of VPA0055 (ChiA2), VP0619 (ChiB), and VPA0832 (Cdx) were essential for the robust growth and high transformation frequency on chitin. The endochitinase, ChiA2, and periplasmic chitinase, Cdx were indispensable for chitin degradation. ChiB was not essential for growth on chitin but did have an effect on the rate of chitin degradation. Interestingly, the loss of Cdx drastically reduced growth on insoluble chitin, but growth on soluble GlcNAc_5/6 remained same. The utilization of GlcNAc_5/6 was only inhibited when there was mutation of Cdx with the other periplasmic chitinases VP0755 and VP2486. This suggests that Cdx might also be involved in extracellular degradation of chitin, in addition to its role as a periplasmic chitinase. Moreover, the periplasmic chitin oligosaccharide-binding protein (CBP) was found to be essential for the efficient utilization of chitin. The CBP was specifically needed for the processing of GlcNAc_4-6 during growth on chitin. Overall, this study provides detailed analysis of the machinery behind chitin degradation in V. parahaemolyticus.

DOI： 10.1139/cjm-2021-0328

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Other Link： https://cdnsciencepub.com/doi/pdf/10.1139/cjm-2021-0328

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

DOI： 10.1111/jam.15594

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jam.15594

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WHO Press  

OBJECTIVE: To evaluate the clinical accuracy of rapid diagnostic tests for the detection of Ebola virus. METHODS: We searched MEDLINE®, Embase® and Web of Science for articles published between 1976 and October 2021 reporting on clinical studies assessing the performance of Ebola virus rapid diagnostic tests compared with reverse transcription polymerase chain reaction (RT-PCR). We assessed study quality using the QUADAS-2 criteria. To estimate the pooled sensitivity and specificity of these rapid diagnostic tests, we used a bivariate random-effects meta-analysis. FINDINGS: Our search identified 113 unique studies, of which nine met the inclusion criteria. The studies were conducted in the Democratic Republic of the Congo, Guinea, Liberia and Sierra Leone and they evaluated 12 rapid diagnostic tests. We included eight studies in the meta-analysis. The pooled sensitivity and specificity of the rapid tests were 86% (95% confidence interval, CI: 80-91) and 95% (95% CI: 91-97), respectively. However, pooled sensitivity decreased to 83% (95% CI: 77-88) after removing outliers. Pooled sensitivity increased to 90% (95% CI: 82-94) when analysis was restricted to studies using the RT-PCR from altona Diagnostics as gold standard. Pooled sensitivity increased to 99% (95% CI: 67-100) when the analysis was restricted to studies using whole or capillary blood specimens. CONCLUSION: The included rapid diagnostic tests did not detect all the Ebola virus disease cases. While the sensitivity and specificity of these tests are moderate, they are still valuable tools, especially useful for triage and detecting Ebola virus in remote areas.

DOI： 10.2471/blt.21.287496

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/jsde.12587

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jsde.12587

Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.2147/idr.s364526

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Background: Approximately 2.9 million people worldwide suffer from cholera each year, many of whom are destitute. However, understanding of immunity against cholera is still limited. Several studies have reported the duration of antibodies following cholera; however, systematic reviews including a quantitative synthesis are lacking. Objective: To meta-analyze cohort studies that have evaluated vibriocidal, cholera toxin B subunit (CTB), and lipopolysaccharide (LPS) antibody levels following a clinical cholera case. Methods: Design: Systematic review and meta-analysis. We searched PubMed and Web of science for studies assessing antibodies against Vibrio cholerae in cohorts of patients with clinical cholera. Two authors independently extracted data and assessed the quality of included studies. Random effects models were used to pool antibody titers in adults and older children (aged ≥ 6 years). In sensitivity analysis, studies reporting data on young children (2–5 years) were included. Results: Nine studies met our inclusion criteria for systematic review and seven for meta-analysis. The pooled mean of vibriocidal antibody titers in adults and older children (aged ≥ 6 years) was 123 on day 2 post-symptom onset, which sharply increased on day 7 (pooled mean = 6956) and gradually waned to 2247 on day 30, 578 on day 90, and 177 on day 360. Anti-CTB IgA antibodies also peaked on day 7 (pooled mean = 49), followed by a rapid decrease on day 30 (pooled mean = 21), and further declined on day 90 (pooled mean = 10), after which it plateaued from day 180 (pooled mean = 8) to 360 (pooled mean = 6). Similarly, anti-CTB IgG antibodies peaked in early convalescence between days 7 (pooled mean = 65) and 30 (pooled mean = 69), then gradually waned on days 90 (pooled mean = 42) and 180 (pooled mean = 30) and returned to baseline on day 360 (pooled mean = 24). Anti-LPS IgA antibodies peaked on day 7 (pooled mean = 124), gradually declined on day 30 (pooled mean = 44), which persisted until day 360 (pooled mean = 10). Anti LPS IgG antibodies peaked on day 7 (pooled mean = 94). Thereafter, they decreased on day 30 (pooled mean = 85), and dropped further on days 90 (pooled mean = 51) and 180 (pooled mean = 47), and returned to baseline on day 360 (pooled mean = 32). Sensitivity analysis including data from young children (aged 2–5 years) showed very similar findings as in the primary analysis. Conclusions: This study confirms that serological antibody (vibriocidal, CTB, and LPS) titers return to baseline levels within 1 year following clinical cholera, i.e., before the protective immunity against subsequent cholera wanes. However, this decay should not be interpreted as waning immunity because immunity conferred by cholera against subsequent disease lasts 3–10 years. Our study provides evidence for surveillance strategies and future research on vaccines and also demonstrates the need for further studies to improve our understanding of immunity against cholera.

DOI： 10.3390/ijerph19127141

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

DOI： 10.1111/jam.15548

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jam.15548

Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

A complex virulence-regulatory cascade controls expression of the cholera toxin genes (ctxAB) in Vibrio cholerae, which eventually leads to the production and secretion of choleragen (CT), responsible for rice watery diarrhoea in infected individuals. The cholera toxin promoter (PctxAB) contains a series of heptad repeats (5′-TTTTGAT-3′), which has previously been shown to play a crucial role in transcriptional regulation of ctxAB by recruiting the transcriptional activators ToxT, ToxR and the nucleoid-associated protein H-NS along the ctx promoter. The number of these repeats differs not only between the two biotypes of V. cholerae O1 strains, but also among the strains belonging to the same biotype. In this study, we examined if regulation of PctxAB is influenced in any way by the number of these repeats. Based on our observations, we posit that ctx activation indeed depends on the number of TTTTGAT heptad repeats within PctxAB, and occupation of the distal repeats by H-NS could prevent transcriptional activation of the ctx genes in V. cholerae O1 pandemic isolates. Our results suggest that ToxT-dependent transcriptional activation may not require entire displacement of H-NS and supports a recently described revised model of ToxT and H-NS mediated PctxAB transcriptional regulation.

DOI： 10.1093/femsle/fnac041

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Other Link： https://academic.oup.com/femsle/article-pdf/369/1/fnac041/43678568/fnac041.pdf

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Fecal contamination of water sources and open defecation have been linked to cholera outbreaks in India. However, a systematic review on the drivers responsible for these outbreaks has yet to be published. Here, we systematically review the published literature on cholera outbreaks in India between 2011 and 2020. We searched studies in English in three databases (MEDLINE, EMBASE, and Web of Science) and the Integrated Disease Surveillance Program that tracks cholera outbreaks throughout India. Two authors independently extracted data and assessed the quality of the included studies. Quantitative data on the modes of transmission reviewed in this study were assessed for any change over time between 2011–2015 and 2016–2020. Our search retrieved 10823 records initially, out of which 81 full-text studies were assessed for eligibility. Among these 81 studies, 20 were eligible for inclusion in this review. There were 565 reported outbreaks between 2011 and 2020 that led to 45,759 cases and 263 deaths. Outbreaks occurred throughout the year; however, they exploded with monsoons (June through September). In Tamil Nadu, a typical peak of cholera outbreaks was observed from December to January. Seventy-two percent (33,089/45,759) of outbreak-related cases were reported in five states, namely Maharashtra, West Bengal, Punjab, Karnataka, and Madhya Pradesh. Analysis of these outbreaks highlighted the main drivers of cholera including contaminated drinking water and food, inadequate sanitation and hygiene (including open defecation), and direct contact between households. The comparison between 2011–2015 and 2016–2020 showed a decreasing trend in the outbreaks that arose due to damaged water pipelines. Many Indians still struggle with open defecation, sanitation, and clean water access. These issues should be addressed critically. In addition, it is essential to interrupt cholera short-cycle transmission (mediated by households, stored drinking water and foodstuffs) during an outbreak. As cholera is associated with deprivation, socio-economic development is the only long-term solution.

DOI： 10.3390/ijerph19095738

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

We sought to summarize knowledge, misconceptions, beliefs, and practices about Ebola that might impede the control of Ebola outbreaks in Africa. We searched Medline, EMBASE, CINAHL, and Google Scholar (through May 2019) for publications reporting on knowledge, attitudes, and practices (KAP) related to Ebola in Africa. In total, 14 of 433 articles were included. Knowledge was evaluated in all 14 articles, and they all highlighted that there are misconceptions and risk behaviors during an Ebola outbreak. Some communities believed that Ebola spreads through the air, mosquito bites, malice from foreign doctors, witchcraft, and houseflies. Because patients believe that Ebola was caused by witchcraft, they sought help from traditional healers. Some people believed that Ebola could be prevented by bathing with salt or hot water. Burial practices where people touch Ebola-infected corpses were common, especially among Muslims. Discriminatory attitudes towards Ebola survivors or their families were also prevalent. Some Ebola survivors were not accepted back in their communities; the possibility of being ostracized from their neighborhoods was high and Ebola survivors had to lead a difficult social life. Most communities affected by Ebola need more comprehensive knowledge on Ebola. Efforts are needed to address misconceptions and risk behaviors surrounding Ebola for future outbreak preparedness in Africa.

DOI： 10.3390/ijerph19084714

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

BACKGROUND: Cholera is an acute diarrheal disease caused by Vibrio cholerae O1 or O139. Cholera rapid diagnostic tests (RDTs) are widely used to screen for cholera cases. However, their accuracy has not been systematically reviewed. OBJECTIVES: To evaluate the diagnostic accuracy of cholera RDTs. METHODS: Systematic review and meta-analysis. DATA SOURCES: Medline, EMBASE and Web of science through to November 2020; references of included studies and a technical guidance on cholera RDTs. This review is registered with PROSPERO (CRD42021233124). STUDY ELIGIBILITY CRITERIA: Cross-sectional studies comparing the performance of cholera RDTs either to stool culture or PCR. PARTICIPANTS: Individuals with clinically suspected cholera. DATA EXTRACTION: Two authors independently extracted data and assessed the quality using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria. RESULTS: Eighteen studies were included in the systematic review of which 17 were used for meta-analysis. Crystal VC was the most frequently used RDT (13 studies), followed by Cholkit and Institut Pasteur cholera dipstick (three studies each), SD Bioline (two studies), Artron (one study) and Smart (one study). Using direct testing (n = 12 627 specimens), the bivariate random-effects model yielded a pooled sensitivity and specificity of 91% (95% CI 87%-94%) and 80% (95% CI 74%-84%), respectively. However, through alkaline peptone water (APW) enrichment (n = 3403 specimens), the pooled sensitivity and specificity were 89% (95% CI 79%-95%) and 98% (95% CI 95%-99%), respectively. CONCLUSION: Cholera RDTs, especially when enriched with APW, have moderate sensitivity and specificity. Although less useful for clinical management, the current generation of RDTs have clear utility for surveillance efforts if used in a principled manner. Enrichment of stool specimens in APW before using cholera RDTs reduces the possibility of obtaining false-positive results, despite the few cholera cases that go undetected. It is noteworthy that APW-enriched cholera RDTs are not necessarily rapid tests, and are not listed in the Global Task Force on Cholera Control/WHO target product profile.

DOI： 10.1016/j.cmi.2021.08.027

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：The Society for Antibacterial and Antifungal Agents, Japan  

DOI： 10.4265/bio.27.57

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Vibrio cholerae can survive cold stress by entering into a viable but non-culturable (VBNC) state, and resuscitation can be induced either by temperature upshift only or the addition of an anti-dormancy stimulant such as resuscitation-promoting factors (Rpfs) at suitable temperature. In this study, the role of proteinase K was analyzed as an Rpf in V. cholerae. A VBNC state was induced in V. cholerae AN59 in artificial seawater (ASW) media at 4 °C, and recovery could be achieved in filtered VBNC microcosm, called spent ASW media, merely by a temperature upshift to 37 °C. The resuscitation ability of spent ASW was further enhanced by the addition of proteinase K. The mode of action of proteinase K was investigated by comparing its effect on the growth of the VBNC and culturable state of V. cholerae in ASW and spent ASW media. The presence of proteinase K allowed culturable cells to grow faster in ASW by reducing the generation time. However, this effect of proteinase K was more pronounced in stressed VBNC cells. Moreover, proteinase K-supplemented spent ASW could also accelerate the transition of VBNC into recovered cells followed by rapid growth. Additionally, we found that dead bacterial cells were the substrate on which proteinase K acts to support high growth in spent ASW. So, the conclusion is that the proteinase K could efficiently promote the recovery and growth of dormant VBNC cells at higher temperatures by decreasing the duration of the initial lag phase required for transitioning from the VBNC to recovery state and increasing the growth rate of these recovered cells.

DOI： 10.3390/microorganisms9122618

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

The rapid diagnosis of cholera contributes to adequate outbreak management. This meta-analysis assesses the diagnostic accuracy of cholera rapid tests (RDTs) to detect Vibrio cholerae O1. METHODS: Systematic review and meta-analysis. We searched four databases (Medline, EMBASE, Google Scholar, and Web of Science up to 8 September 2021) for studies that evaluated cholera RDTs for the detection of V. cholerae O1 compared with either stool culture or polymerase chain reaction (PCR). We assessed the studies' quality using the QUADAS-2 criteria. In addition, in this update, GRADE approach was used to rate the overall certainty of the evidence. We performed a bivariate random-effects meta-analysis to calculate the pooled sensitivity and specificity of cholera RDTs. RESULTS: Overall, 20 studies were included in this meta-analysis. Studies were from Africa (n = 11), Asia (n = 7), and America (Haiti; n = 2). They evaluated eight RDTs (Crystal VC-O1, Crystal VC, Cholkit, Institut Pasteur cholera dipstick, SD Bioline, Artron, Cholera Smart O1, and Smart II Cholera O1). Using direct specimen testing, sensitivity and specificity of RDTs were 90% (95% CI, 86 to 93) and 86% (95% CI, 81 to 90), respectively. Cholera Sensitivity was higher in studies conducted in Africa [92% (95% CI, 89 to 94)] compared with Asia [82% (95% CI, 77 to 87)]. However, specificity [83% (95% CI, 71 to 91)] was lower in Africa compared with Asia [90% (95% CI, 84 to 94)]. GRADE quality of evidence was estimated as moderate. CONCLUSIONS: Against culture or PCR, current cholera RDTs have moderate sensitivity and specificity for detecting Vibrio cholerae O1.

DOI： 10.3390/diagnostics11112095

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00705-021-05197-6

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Other Link： https://link.springer.com/article/10.1007/s00705-021-05197-6/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Cholera toxin (CT)-producing Vibrio cholerae O1 and O139 cause acute diarrheal disease and are proven etiological agents of cholera epidemics and pandemics. On the other hand, V. cholerae non-O1/non-O139 are designated as non-agglutinable (NAG) vibrios and are not associated with epidemic cholera. The majority of NAG vibrios do not possess the gene for CT (ctx). In this study, we isolated three NAG strains (strains No. 1, 2, and 3) with ctx from pond water in Kolkata, India, and examined their pathogenic properties. The enterotoxicity of the three NAG strains in vivo was examined using the rabbit ileal intestinal loop test. Strain No. 1 induced the accumulation of fluid in the loop, and the volume of fluid was reduced by simultaneous administration of anti-CT antiserum into the loop. The volume of fluid in the loop caused by strains No. 2 and 3 was small and undetectable, respectively. Then, we cultured these three strains in liquid medium in vitro at two temperatures, 25°C and 37°C, and examined the amount of CT accumulated in the culture supernatant. CT was accumulated in the culture supernatant of strain No.1 when the strain was cultured at 25°C, but that was low when cultured at 37°C. The CT amount accumulated in the culture supernatants of the No. 2 and No. 3 strains was extremely low at both temperature under culture conditions examined. In order to clarify the virulence properties of these strains, genome sequences of the three strains were analyzed. The analysis showed that there was no noticeable difference among three isolates both in the genes for virulence factors and regulatory genes of ctx. However, vibrio seventh pandemic island-II (VSP-II) was retained in strain No. 1, but not in strains No. 2 or 3. Furthermore, it was revealed that the genotype of the B subunit of CT in strain No. 1 was type 1 and those of strains No. 2 and 3 were type 8. Histopathological examination showed the disappearance of villi in intestinal tissue exposed to strain No. 1. In addition, fluid accumulated in the loop due to the action of strain No. 1 had hemolytic activity. This indicated that strain No. 1 may possesses virulence factors to induce severe syndrome when the strain infects humans, and that some strains of NAG vibrio inhabiting pond water in Kolkata have already acquired virulence, which can cause illness in humans. There is a possibility that these virulent NAG vibrios, which have acquired genes encoding factors involved in virulence of V. cholerae O1, may emerge in various parts of the world and cause epidemics in the future.

DOI： 10.3389/fmicb.2021.726273

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s11274-021-03113-3

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Other Link： https://link.springer.com/article/10.1007/s11274-021-03113-3/fulltext.html

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

Cholera is an acute diarrheal disease caused by pathogenic strains of V. cholerae generated by lysogenization of the filamentous cholera toxin phage CTXΦ. The analysis revealed that recent isolates possessed altered CTXΦ prophage array of prototype El Tor strain and were defective in replicating the CTXΦ genome.

DOI： 10.1128/msphere.00337-21

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：The Society for Antibacterial and Antifungal Agents, Japan  

DOI： 10.4265/bio.26.113

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Publishing type：Research paper (scientific journal)   Publisher：The Society for Free Radical Research Japan  

DOI： 10.3164/jcbn.20-201

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

DOI： 10.3389/fcimb.2020.572096

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

DOI： 10.1111/1348-0421.12829

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/1348-0421.12829

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Vibrios can degrade chitin surfaces to soluble N-acetyl glucosamine oligosaccharides (GlcNAcn) that can be utilized as a carbon source and also induce a state of natural genetic competence. In this study, we characterized chitin-dependent growth and natural competence in Vibrio parahaemolyticus and its regulation. We found that growth on chitin was regulated through chitin sensors ChiS (sensor histidine kinase) and TfoS (transmembrane transcriptional regulator) by predominantly controlling the expression of chitinase VPA0055 (ChiA2) in a TfoX-dependent manner. The reduced growth of ΔchiA2, ΔchiS and ΔtfoS mutants highlighted the critical role played by ChiA2 in chitin breakdown. This growth defect of ΔchiA2 mutant could be recovered when chitin oligosaccharides GlcNAc2 or GlcNAc6 were supplied instead of chitin. The ΔtfoS mutant was also able to grow on GlcNAc2 but the ΔchiS mutant could not, which indicates that GlcNAc2 catabolic operon is dependent on ChiS and independent of TfoS. However, the ΔtfoS mutant was unable to utilize GlcNAc6 because the periplasmic enzymes required for the breakdown of GlcNAc6 were found to be downregulated at the mRNA level. We also showed that natural competence can be induced only by GlcNAc6, not GlcNAc2, because the expression of competence genes was significantly higher in the presence of GlcNAc6 compared to GlcNAc2. Moreover, this might be an indication that GlcNAc2 and GlcNAc6 were detected by different receptors. Therefore, we speculate that GlcNAc2-dependent activation of ChiS and GlcNAc6-dependent activation of TfoS might be crucial for the induction of natural competence in V. parahaemolyticus through the upregulation of the master competence regulator TfoX.

DOI： 10.3390/microorganisms8091303

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

It has been well known that Vibrio cholerae inhabit in environmental water. As many patients infected with cholera toxin-producing V. cholerae O1 (toxigenic V. cholerae O1) emerge in Kolkata, India, it has been thought that toxigenic V. cholerae O1 is easily detected in environmental water in Kolkata. However, we could not isolate toxigenic V. cholerae O1 from environmental water in Kolkata, though NAG Vibrio (generic name of V. cholerae non-O1/non-O139) is constantly detected. To clear the reason for the non-isolation of toxigenic V. cholerae O1, we examined the viability of V. cholera O1 and NAG Vibrios in the artificial low ionic strength aquatic solution. We found that the viability of toxigenic V. cholerae O1 in the solution is low, but that of NAG Vibrios is high. Subsequently, we examined the viability of NAG Vibrios possessing cholera toxin gene (ctx) in the same condition and found that the viability of these NAG Vibrios is low. These results indicate that the existence of ctx in V. cholerae affects the viability of V. cholerae in the aquatic solution used in this experiment. We thought that there was closely relation between the low viability of toxigenic V. cholerae O1 in the artificial low ionic strength aquatic solution and the low frequency of isolation of the strain from environmental water.

DOI： 10.1248/bpb.b20-00350

PubMed

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

Non-O1/non-O139 nontoxigenic Vibrio cholerae associated with cholera-like diarrhea has been reported in Kolkata, India. However, the property involved in the pathogenicity of these strains has remained unclear. The character of 25 non-O1/non-O139 nontoxigenic V. cholerae isolated during 8 years from 2007 to 2014 in Kolkata was examined. Determination of the serogroup showed that the serogroups O6, O10, O35, O36, O39, and O70 were represented by two strains in each serogroup, and the remaining isolates belonged to different serogroups. To clarify the character of antibiotic resistance of these isolates, an antibiotic resistance test and the gene analysis were performed. According to antimicrobial drug susceptibility testing, 13 strains were classified as drug resistant. Among them, 10 strains were quinolone resistant and 6 of the 13 strains were resistant to more than three antibiotics. To define the genetic background of the antibiotic character of these strains, whole-genome sequences of these strains were determined. From the analysis of these sequences, it becomes clear that all quinolone resistance isolates have mutations in quinolone resistance-determining regions. Further research on the genome sequence showed that four strains possess Class 1 integrons in their genomes, and that three of the four integrons are found to be located in their genomic islands. These genomic islands are novel types. This indicates that various integrons containing drug resistance genes are spreading among V. cholerae non-O1/non-O139 strains through the action of newly generated genomic islands.

DOI： 10.1111/1348-0421.12790

PubMed

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

DOI： 10.1016/j.gene.2019.144016

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1186/s41182-019-0167-4

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Other Link： http://link.springer.com/article/10.1186/s41182-019-0167-4/fulltext.html

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DOI： 10.1099/mic.0.000798

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DOI： 10.1016/j.pep.2018.04.004

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DOI： 10.4265/bio.22.229

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DOI： 10.1371/journal.pntd.0005386

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DOI： 10.1111/1348-0421.12465

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DOI： 10.1002/jobm.201600002

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DOI： 10.1248/bpb.b15-00708

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DOI： 10.4265/bio.20.263

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DOI： 10.4265/bio.20.199

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DOI： 10.1111/lam.12429

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DOI： 10.1111/1348-0421.12246

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DOI： 10.4265/bio.20.77

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DOI： 10.4265/bio.19.199

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DOI： 10.1111/1348-0421.12177

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DOI： 10.1016/j.mimet.2014.06.011

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DOI： 10.1002/mbo3.164

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DOI： 10.1007/s11274-013-1501-3

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DOI： 10.1016/j.aquaculture.2013.09.041

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DOI： 10.4265/bio.18.53

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DOI： 10.3389/fmicb.2013.00339

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DOI： 10.1016/B978-0-12-382219-2.00119-8

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Publishing type：Research paper (scientific journal)   Publisher：Okayama Medical Association  

DOI： 10.4044/joma.125.35

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DOI： 10.1007/s11274-012-1030-5

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DOI： 10.1111/j.1348-0421.2012.00440.x

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DOI： 10.1007/s11274-011-0969-y

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DOI： 10.1111/j.1348-0421.2011.00405.x

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DOI： 10.1016/j.ijfoodmicro.2011.07.006

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DOI： 10.1016/j.toxicon.2011.03.013

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DOI： 10.4265/bio.16.1

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DOI： 10.1248/jhs.56.618

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DOI： 10.1016/j.ijfoodmicro.2010.07.034

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DOI： 10.4265/bio.15.1

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DOI： 10.1248/jhs.55.820

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DOI： 10.1111/j.1742-4658.2008.06827.x

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DOI： 10.1248/jhs.54.686

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DOI： 10.1111/j.1574-6968.2008.01159.x

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DOI： 10.1016/j.micpath.2008.01.001

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DOI： 10.4265/bio.13.1

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DOI： 10.1016/j.micpath.2007.07.002

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DOI： 10.1248/jhs.53.750

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DOI： 10.1248/jhs.53.430

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DOI： 10.1248/jhs.53.185

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DOI： 10.1111/j.1462-5822.2006.00809.x

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DOI： 10.1111/j.1346-8138.2006.00139.x

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DOI： 10.1007/s00253-005-0194-4

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DOI： 10.1080/15569540500320862

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Bacteriology  

DOI： 10.3412/jsb.61.261

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Language：English   Publishing type：Part of collection (book)   Publisher：Elsevier Inc.  

DOI： 10.1016/B978-012088445-2/50049-4

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DOI： 10.1099/jmm.0.45908-0

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DOI： 10.1016/j.toxicon.2004.08.013

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DOI： 10.1248/jhs.50.605

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DOI： 10.1016/j.femsle.2004.09.023

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DOI： 10.1016/j.micpath.2003.10.001

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DOI： 10.1081/TXR-120030650

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Antibacterial and Antifungal Agents Japan  

DOI： 10.4265/bio.9.89

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DOI： 10.1128/JB.185.23.6938-6949.2003

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DOI： 10.1046/j.1462-2920.2003.00458.x

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DOI： 10.1016/S0024-3205(03)00094-8

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DOI： 10.1128/IAI.71.1.533-535.2003

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DOI： 10.1006/mpat.2002.0520

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DOI： 10.1016/S0378-1097(02)00741-3

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DOI： 10.1128/jb.184.4.936-946.2002

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DOI： 10.1016/S0378-1097(02)00448-2

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DOI： 10.1016/S0378-1097(02)00449-4

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DOI： 10.4265/bio.7.37

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DOI： 10.1016/S0041-0101(01)00171-4

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Language：Japanese   Publisher：岡山大学環境計測共同利用施設  

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DOI： 10.1111/j.1348-0421.2001.tb01292.x

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DOI： 10.4265/bio.6.81

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DOI： 10.1248/jhs.46.187

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DOI： 10.1248/bpb.23.649

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DOI： 10.1006/abbi.2000.1784

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DOI： 10.1016/S1286-4579(00)00280-X

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DOI： 10.1248/jhs.46.63

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Authorship：Lead author   Language：Japanese   Publisher：Pharmaceutical Society of Japan  

DOI： 10.1248/yakushi1947.120.11_1149

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Antibacterial and Antifungal Agents Japan  

DOI： 10.4265/bio.5.111

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DOI： 10.4265/bio.5.117

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DOI： 10.1139/cjm-45-10-833

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DOI： 10.1006/abbi.1999.1321

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DOI： 10.1016/S0378-1097(99)00016-6

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：JAPANESE SOCIETY FOR BACTERIOLOGY  

DOI： 10.3412/jsb.54.763

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Vibrio parahaemolyticus strains isolated from different sources were assayed for their ability to produce a siderophore, vibrioferrin, under iron-limited growth conditions. The mean value } standard error of mean (μM vibrioferrin in spent culture supernatant/optical density at 660nm) was 832.3 } 66.9 for clinical isolates (n 44), which was significantly higher (P 0.01) than those for food isolates (461.0 } 66.5; n 37) and coastal isolates (378.8 } 37.2; n 26). This suggests that greater productivity of vibrioferrin by clinical isolates may be associated with a selective advantage for survival and proliferation under conditions of iron-limitation such as in the intestine.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

DOI： 10.1128/iai.66.10.4851-4855.1998

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DOI： 10.1007/BF02770805

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DOI： 10.1006/mpat.1997.0149

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Authorship：Last author   Language：Japanese   Publisher：The Pharmaceutical Society of Japan  

The first recognized outbreaks of hemorrhagic colitis occurred in 1982 in the United State and its etiologic agent was identified to be Escherichia coli O157 : H7,a serotype not previously associated with diseases in humans. In Japan, isolates of the serotype O157 : H7 from contaminated drinking water were first implicated in an outbreak occurred in 1990 in a kindergarten of the Saitama Prefecture, and at least other 12 such outbreaks have been recorded in 1993-1995. In the year 1996,unprecedentedly large outbreaks and many sporadic cases of disease caused by E. coli O157 : H7 occurred in various parts of Japan, affecting more than 9000 people in total (11 deaths). In most cases, however, the ultimate source of the infection could not be traced. Although many different serotypes of E. coli, which are collectively referred to as enterohemorrhagic E. coli (EHEC), were found to cause bloody diarrhea, the serotype O157 : H7 has been recognized worldwide as the pathogen associated most frequently with serious complications known as hemolytic colitis and hemolytic uremic syndrome. E. coli O157 : H7 is characteristic of a low infectious dose, on the order of a few hundred organisms, which contributes to the spread of the infection in outbreak situations. Cattle are considered to be the major reservoir of EHEC including O157 : H7. EHEC strains produce at least two immunologically distinct cytotoxins that closely resemble the Shiga toxin produced by the Shigella dysenteriae type 1 strains. These toxins (called Shiga-like toxins or Vero toxins) appear to be responsible for causing many pathological effects associated with EHEC infections. However, how the toxins move from the intestinal tract lumen to the sites where they damage the kidney remains to be evaluated. Moreover, there are some doubts about the value of antibiotic therapy in such infections because of the observation that some antibiotics can increase the toxin expression in vitro and because of the concern that EHEC which are lysing due to their actions in the gastrointestinal tract lumen may actually release more toxin than do intact bacterial cells. Unique biochemical characteristics of E. coli O157 : H7-it ferments sorbitol very slowly and usually does not make β-glucuronidase- are used to differentiate this strain from other enteric E. coli strains. Alternative methods based on the detection of the toxins themselves by enzyme immunoassay are employed in parallel. This review describes the current understanding of the infectious disease caused by E. coli O157 : H7,with an emphasis on the main diagnostic tests and epidemiology for this serotype and the role of the toxins in pathogenesis.

DOI： 10.1248/jhs1956.43.1

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Other Link： http://search.jamas.or.jp/link/ui/1997166835

Authorship：Lead author,　Corresponding author  

DOI： 10.3109/15569549709016455

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Language：English   Publisher：Center For Academic Publications Japan  

An environmental isolate of V. mimicus, strain E-33, has been reported to produce and secrete a hemolysin of 63kDa. The hemolysin is enterotoxic in test animals. The nucleotide sequence of the structural gene of the hemolysin was determined. We found a 2, 232bp open reading frame, which codes a peptide of 744 amino acids, with a calculated molecular weight of 83, 903 Da. The sequence for the structural gene was closely related to the V. cholerae el for hlyA gene, coding an exocellular hemolysin. The amino terminal amino-acid sequence of the 63kDa hemolysin, purified from V. mimicus, was determined by the Edman degradation method and found to be NH₂=-S-V-S-A-N-N-V-T-N-N-N-E-T. This sequence is identical from S-152 to T-164 predicted from the nucleotide sequence. So, it seems that the mature hemolysin in V. mimicus is processed upon deleting the first 151 amino acids, and the molecular mass is 65, 972 Da. Analyzing the deduced amino-acid sequence, we also found a potential signal sequence of 24 amino acids at the amino terminal. Our results suggest that, like V. cholerae hemolysin, two-step processing also exists in V. mimicus hemolysin.

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Authorship：Lead author  

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Language：English   Publisher：Center For Academic Publications Japan  

In vitro growth experiments were conducted to evaluate the ability of vulnibactin, a siderophore produced by Vibrio vulnificus, to sequester transferrin- or lactoferrin-bound iron for growth. Comparative studies with the strain producing vulnibactin and its exocellular protease-deficient mutant revealed the involvement of the protease in addition to vulnibactin in effective utilization of iron ion (Fe³⁺) bound to transferrin and lactoferrin. It appears that the protease causes cleavage of these proteins, thereby making bound iron more accessible to vulnibactin.

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

DOI： 10.1128/iai.64.10.4035-4041.1996

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

DOI： 10.1128/aem.62.10.3871-3874.1996

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Authorship：Lead author   Language：English  

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Language：English   Publisher：Center For Academic Publications Japan  

Exocellular proteases produced by Vibrio fluvialis, V. furnissii, V. metschnikovii and V. campbellii were characterized and compared to those of V. mimicus protease (VMP) and V. vulnfcus protease (VVP). These proteases possessed both elastolytic and hemagglutinating abilities and were identified, except that of V. metschnikovii, as metalloprotease. Conversely, V. metschnikovii protease failed to exhibit some of the salient features for metalloproteases suggesting the existence of protease(s) other than metalloprotease. However, antibodies against VVP cross-reacted to these proteases and to VMP indicating antigenic relatedness amongst vibrio proteases. This study, thus, demonstrated the prevalent distributions of antigenically related proteases both in pathogenic and non-pathogenic vibrios, bringing their status as a virulence determinant into question.

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Other Link： http://search.jamas.or.jp/link/ui/1996104022

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Kluwer Academic Publishers  

DOI： 10.1007/BF00140480

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Language：English   Publisher：Center For Academic Publications Japan  

The protease elaborated by Vibrio mimicus is known to possess hemagglutinating ability to chicken erythrocytes, the well-known HA/protease. A non-protease hemagglutinin (HA) with strong agglutinating ability towards rabbit erythrocytes was obtained from 32hr culture supernatant of a pathogenic environmental strain of V. mimicus. This HA (V. mimicus HA: VMHA) appeared stable at relatively higher temperature and agglutinated the erythrocytes from rabbit, guinea pig and mouse but not the erythrocytes from chicken, bovine, horse and sheep. Simple sugars, metal ions and chelating agents failed to inhibit the activity of VMHA. The activity of VMHA was found to be sensitive to digestion by proteolytic enzymes including HA/protease. These results provide evidence for the existence of novel HA other than HA/protease in V. mimicus.

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

DOI： 10.1002/yea.320100306

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A Vibrio vulnificus hemolysin (VVH) was purified by two steps of hydrophobic column chromatography on Phenyl-Sepharose HP. The first chromatography was carried out at pH 6.0. In this pH condition, VVH efficiently bound to the column, but the hemolysin fraction eluted was accompanied with colored substance(s). To eliminate this colored substance, the second chromatography was carried out at pH 9.8 in the presence of 1% 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS), a zwitterionic detergent. Homogeneity of the hemolysin thus obtained was shown by polyacrylamide gel electrophoresis. The specific activity increased 33, 600 times and the yield was 35%. The method is simple and useful to supply enough VVH for study of the role of the hemolysin in the infection by V. vulnificus or on the mechanism of action of the hemolysin.

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Language：English   Publisher：Center For Academic Publications Japan  

Some properties and mechanism of action of a hemolysin (VMH) produced by an enteropathogenic Vibrio mimicus strain was examined. VMH was heat-labile and inhibited by addition of divalent cations, including Ca²⁺, Mg²⁺ and Mn²⁺. The hemolysis by VMH was inhibited by incubating with gangliosides, suggesting that the ganglioside was the binding site on the erythrocyte membrane for VMH. Existence of a galactose moiety on reducing end of the ganglioside molecule and a sialic acid on the galactose moiety was suggested to be important for the binding of VMH molecule. Colloid osmotic manner of the hemolysis by VMH was demonstrated.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa Healthcare  

DOI： 10.3109/15569549309014409

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Authorship：Lead author   Language：English   Publisher：The Japanese Biochemical Society  

The metalloprotease produced by Vibrio vulnificus (VVP) is known to be quickly inactivated by plasma proteins which belong to the class of α-macroglobulins in vitro at a molar ratio of 1:1. But the in vivo potential of the inactivators has not been studied. Macroalbumin (MA), a member of a -macroglobulins in guinea pig plasma, was found to inactivate VVP by means of physical entrapment in vitro. In vivo actions of VVP, permeability-enhancing and hemorrhagic actions, were greatly augmented by simultaneous injection of the antibody against MA, which had no effect on in vitro proteolytic action toward azocasein. The interstitial-tissue space in the normal guinea pig skin contains a negligible amount of MA. However, sufficient MA was present in the extravascular fluid collected after the intradermal injection of VVP. Besides, in the extravascular fluid, VVP formed a complex with MA and no inactivator other than MA was found. These results indicate that plasma MA leaked from the vascular system owing to the permeability-enhancing and hemorrhagic actions of VVP, resulting in inactivation of VVP in situ.

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Language：English   Publisher：Center For Academic Publications Japan  

Vibrio mimicus, a causative agent of gastroenteritis, has also been reported to attribute to extraintestinal infections. Recently we have purified a metalloprotease produced by the pathogen: however, the role of the protease in V. mimicus infection has not been documented. The V. mimicus protease (VMP) was found to enhance vascular permeability and form edema when injected into the dorsal skin of guinea pig and rat. The permeability enhancement by VMP was observed in a dose-dependent manner in both guinea pig and rat skin. In guinea pig, an inhibitor of the angiotensin-converting enzyme was found to augment the permeability enhancement reaction. The permeability enhancement was significantly blocked by soybean trypsin inhibitor (SBTI), an inhibitor of plasma kallikrein reaction. In vitro conversion of plasma prekallikrein to kallikrein by VMP was also noted. In rat skin, the permeability enhancement reaction was not blocked by antihistamine or SBTI. However, the reaction was partially blocked when a mixture of antihistamine and SBTI was administered with VMP. It is apparent from the study that in guinea pig skin, VMP enhances vascular permeability through activation of plasma kallikrein-kinin system which generates bradykinin, whereas in addition to the activation of plasma kallikrein-kinin cascade in the case of rat, stimulation of histamine release from mast cells and other unknown mechanism seem to be also a cause of the permeability enhancement reaction. These results suggest that VMP may play a role in extraintestinal infections with edema caused by the pathogen.

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

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DOI： 10.1111/j.1574-6968.1990.tb04046.x

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Authorship：Lead author   Language：English   Publishing type：Research paper (international conference proceedings)  

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Authorship：Lead author   Language：English   Publisher：The Japanese Biochemical Society  

Vibrio vulnificus, an etiologic agent of wound infections and septicemia in humans, elaborates a metalloprotease which is known to be an important virulence factor of the Vibrio. The proteolytic activity of V. vulnificus metalloprotease (VVP) toward casein and elastin was inhibited by α₂-macroglobulin (α₂ M) at the molar ratio of 1:1, although partial activity was maintained. Permeability-enhancing and hemorrhagic activities were also inhibited, but the peptidase activity toward Z-Gly-Phe-NH₂ was not reduced, even by an excess amount of α₂ M. VVP formed a complex with α₂ M through cleavage of the bait regions of all four α₂ M subunits and elicitation of conformational change of the α₂M molecule, which resulted in entrapment of VVP in the α₂ M molecule. The peptidase activity of α₂ M-VVP complex was inhibited by low-molecular-weight inhibitors such as phosphoramidon, but IgG antibody against VVP failed to neutralize its peptidase activity. Of human plasma proteins, α₂ M was the only inhibitor for VVP. These findings indicate that VVP produced during V. vulnificus infection is inactivated by plasma α₂ M that leaks from the vascular system.

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

DOI： 10.1128/aem.55.8.2073-2078.1989

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Authorship：Lead author   Language：English   Publisher：Center For Academic Publications Japan  

The protease produced by Vibrio vulnifrcus enhances vascular permeability through histamine release from mast cells and activation of the plasma kallikrein-kinin system which generates bradykinin when injected into the dorsal skin. V. vulnificus living cells also enhanced vascular permeability within a few hours after the injection into the dorsal skin. The permeability-enhancing activity of living cells was greatly reduced by addition of soybean trypsin inhibitor, a specific inhibitor for plasma kallikrein-kinin system, or anti-protease IgG. Two protease-deficient mutants induced by nitrosoguanidine treatment had only one-tenth permeability-enhancing activity of a wild-type strain. These results indicate that V. vulnificus elaborates the protease in vivo and that the protease elaborated enhances vascular permeability through release of chemical mediators such as histamine and bradykinin and forms edema.

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Language：English   Publisher：Center For Academic Publications Japan  

A protease was purified from a strain of Vibrio vulnificus isolated from the blood of a septicemic human. The vibrio was cultured in bacto peptone-yeast extract medium, and the protease was purified by a purification procedure including ultrafiltration of the culture supernatant with an Amicon YM 5 membrane, diethylaminoethyl-Sephacel column chromatography, Sephacryl S-200 column chromatography and fast protein liquid chromatography on Mono Q column. The protease preparation revealed homogeneity on polyacrylamide gel electrophoresis and about 30, 000-fold purification was achieved, with a yield of about 30%. The isoelectric point of the purified V. vulnificus protease was about 5.80 and its molecular weight was ca. 45, 000 by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The optimum pH of the protease activity was 8.0. The V. vulnificus protease was inhibited by a metalloprotease inhibitor and zinc ion and/or ferrous ion were essential for its enzyme activity. No cysteine residue was detected in the V. vulnificus protease. The protease had caseinolytic, elastolytic and collagenolytic activities.

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

DOI： 10.1111/j.1574-6968.1987.tb01989.x

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

DOI： 10.1111/j.1574-6968.1986.tb01425.x

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Language：Japanese   Publisher：The Pharmaceutical Society of Japan  

Distribution of diarrhenogenic species of genus Vibrio in estuarine area of Ohta River, Hiroshima, and Asahi River, Okayama, was investigated. Diarrhenogenic vibrios, such as Vibrio parahaemolyticus, V. fluvialis or NAG vibrio, inhabit in estuarine region. Because the former two vibrios are slightly halophilic, they cannot survive in fresh water. However, the number of V. parahaemolyticus detected in brackish water area of the river was much more than that of sea region. In brackish water area, the salinity was lower than optimal concentration for the vibrio because sea water was mixed with fresh water, but nutrient salts content, such as phosphate and nitrogen compounds, was higher than that of sea region. These nutrient salts seemed to stimulate a growth of the vibrios in estuarine region. The number of V. fluvialis was variable and in some sampling points, its number was comparable to the number of V. parahaemolyticus. NAG vibrio was also widely distributed in the estuarine region investigated, but the number was fewer than that of V. parahaemolyticus or V. fluvialis

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Language：English   Publisher：Center For Academic Publications Japan  

Some properties of he nolysin produced by Vibrio vulnificus were investigated. The hemolysin was heat labile, and the hemolytic activity was inhibited by adding cholesterol or divalent cations. Cholesterol inhibited the temperature-independent hemolysin-binding step, suggesting that cholesterol made up the binding site. of the cell membrane, whereas the divalent cations inhibited the temperature-dependent membrane-degradation step. However, the V. vulnificus hemolysin was stable to oxygen and sulfhydryl reagents and was not inactivated by antiserum against streptolysin O, suggesting that the V. vulnificus hemolysin differs from oxygen-labile hemolysins which bind to cholesterol. The V. vulnificus hemolysin seems to be one of the exceptional cholesterol-binding hemolysins.

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Language：English   Publisher：日本細菌学会  

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：Japanese   Publisher：(株)近代出版  

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：English   Publisher：The Pharmaceutical Society of Japan  

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Language：English   Publisher：The Pharmaceutical Society of Japan  

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Event date： 2019.9.5 - 2019.9.6

Language：English   Presentation type：Oral presentation (general)  

Venue：Sapporo, Japan  

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Event date： 2019.9.5 - 2019.9.6

Language：English   Presentation type：Poster presentation  

Venue：Sapporo, Japan  

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Event date： 2019.9.5 - 2019.9.6

Language：English   Presentation type：Oral presentation (general)  

Venue：Sapporo, Japan  

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