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      A Novel Mouse Model of Campylobacter jejuni Gastroenteritis Reveals Key Pro-inflammatory and Tissue Protective Roles for Toll-like Receptor Signaling during Infection

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          Abstract

          Campylobacter jejuni is a major source of foodborne illness in the developed world, and a common cause of clinical gastroenteritis. Exactly how C. jejuni colonizes its host's intestines and causes disease is poorly understood. Although it causes severe diarrhea and gastroenteritis in humans, C. jejuni typically dwells as a commensal microbe within the intestines of most animals, including birds, where its colonization is asymptomatic. Pretreatment of C57BL/6 mice with the antibiotic vancomycin facilitated intestinal C. jejuni colonization, albeit with minimal pathology. In contrast, vancomycin pretreatment of mice deficient in SIGIRR ( Sigirr −/− ), a negative regulator of MyD88-dependent signaling led to heavy and widespread C. jejuni colonization, accompanied by severe gastroenteritis involving strongly elevated transcription of Th1/Th17 cytokines. C. jejuni heavily colonized the cecal and colonic crypts of Sigirr −/− mice, adhering to, as well as invading intestinal epithelial cells. This infectivity was dependent on established C. jejuni pathogenicity factors, capsular polysaccharides ( kpsM) and motility/flagella ( flaA). We also explored the basis for the inflammatory response elicited by C. jejuni in Sigirr −/− mice, focusing on the roles played by Toll-like receptors (TLR) 2 and 4, as these innate receptors were strongly stimulated by C. jejuni. Despite heavy colonization, Tlr4 −/−/Sigirr −/− mice were largely unresponsive to infection by C. jejuni, whereas Tlr2 −/−/Sigirr −/− mice developed exaggerated inflammation and pathology. This indicates that TLR4 signaling underlies the majority of the enteritis seen in this model, whereas TLR2 signaling had a protective role, acting to promote mucosal integrity. Furthermore, we found that loss of the C. jejuni capsule led to increased TLR4 activation and exaggerated inflammation and gastroenteritis. Together, these results validate the use of Sigirr −/− mice as an exciting and relevant animal model for studying the pathogenesis and innate immune responses to C. jejuni.

          Author Summary

          Research into the key virulence strategies of the bacterial pathogen Campylobacter jejuni, as well as the host immune responses that develop against this microbe have, in many ways, been limited by the lack of relevant animal models. Here we describe the use of Sigirr deficient ( −/− ) mice as a model for C. jejuni pathogenesis. Not only do Sigirr −/− mice develop significant intestinal inflammation in response to colonization by C. jejuni, but the ability of this pathogen to trigger gastroenteritis was dependent on key virulence factors. We also found that the induction of the inflammatory and Th1/Th17 immune responses to infection in these mice depended on specific Toll-like receptors, principally TLR4, which we identified as the main driver of inflammation. In contrast, TLR2 signaling was found to protect mucosal integrity, with Tlr2 −/−/Sigirr −/− mice suffering exaggerated mucosal damage and inflammation. Notably, we found that C. jejuni's capsule helped conceal it from the host's immune system as its loss led to significantly increased activation of host TLRs and exaggerated gastroenteritis. Our research shows that the increased sensitivity of Sigirr −/− mice can be used to generate a unique and exciting model that facilitates the study of C. jejuni pathogenesis as well as host immunity to this enteric pathogen.

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          Most cited references52

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          Gut inflammation provides a respiratory electron acceptor for Salmonella

          Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. The inflammatory response enhances the transmission success of S. Typhimurium by promoting its outgrowth in the gut lumen through unknown mechanisms. Here we show that reactive oxygen species generated during inflammation reacted with endogenous, luminal sulphur compounds (thiosulfate) to form a new respiratory electron acceptor, tetrathionate. The genes conferring the ability to utilize tetrathionate as an electron acceptor produced a growth advantage for S. Typhimurium over the competing microbiota in the lumen of the inflamed gut. We conclude that S. Typhimurium virulence factors induce host-driven production of a new electron acceptor that allows the pathogen to use respiration to compete with fermenting gut microbes. Thus, the ability to trigger intestinal inflammation is crucial for the biology of this diarrhoeal pathogen.
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            Assessment of soil microbial community structure by use of taxon-specific quantitative PCR assays.

            Here we describe a quantitative PCR-based approach to estimating the relative abundances of major taxonomic groups of bacteria and fungi in soil. Primers were thoroughly tested for specificity, and the method was applied to three distinct soils. The technique provides a rapid and robust index of microbial community structure.
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              Campylobacter jejuni: a brief overview on pathogenicity-associated factors and disease-mediating mechanisms.

              Campylobacter jejuni has long been recognized as a cause of bacterial food-borne illness, and surprisingly, it remains the most prevalent bacterial food-borne pathogen in the industrial world to date. Natural reservoirs for this Gram-negative, spiral-shaped bacterium are wild birds, whose intestines offer a suitable biological niche for the survival and dissemination of C. jejuni Chickens become colonized shortly after birth and are the most important source for human infection. In the last decade, effective intervention strategies to limit infections caused by this elusive pathogen were hindered mainly because of a paucity in understanding the virulence mechanisms of C. jejuni and in part, unavailability of an adequate animal model for the disease. However, recent developments in deciphering molecular mechanisms of virulence of C. jejuni made it clear that C. jejuni is a unique pathogen, being able to execute N-linked glycosylation of more than 30 proteins related to colonization, adherence, and invasion. Moreover, the flagellum is not only depicted to facilitate motility but as well secretion of Campylobacter invasive antigens (Cia). The only toxin of C. jejuni, the so-called cytolethal distending toxin (CdtA,B,C), seems to be important for cell cycle control and induction of host cell apoptosis and has been recognized as a major pathogenicity-associated factor. In contrast to other diarrhoea-causing bacteria, no other classical virulence factors have yet been identified in C. jejuni. Instead, host factors seem to play a major role for pathogenesis of campylobacteriosis of man. Indeed, several lines of evidence suggest exploitation of different adaptation strategies by this pathogen depending on its requirement, whether to establish itself in the natural avian reservoir or during the course of human infection. (c) 2009 Elsevier GmbH. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                July 2014
                17 July 2014
                : 10
                : 7
                : e1004264
                Affiliations
                [1 ]Division of Gastroenterology, British Columbia Children's Hospital, the Child and Family Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
                [2 ]Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
                [3 ]Department of Pediatrics, British Columbia Children's Hospital and Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
                [4 ]Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
                University of Michigan Medical School, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MS JR JV HY BAV. Performed the experiments: MS JR JV HY HPS SMC YB. Analyzed the data: MS JR JV HY HPS SMC YB BAV. Contributed reagents/materials/analysis tools: JV HPS SET ECG XL BAV. Contributed to the writing of the manuscript: MS JR JV HY HPS SMC YB ECG BAV.

                ¶ ECG and XL also contributed equally to this work.

                Article
                PPATHOGENS-D-14-00611
                10.1371/journal.ppat.1004264
                4102570
                25033044
                255ccdc0-a848-44f3-940f-7437666d97a0
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 March 2014
                : 6 June 2014
                Page count
                Pages: 16
                Funding
                The work by BAV was supported by operating grants from the Canadian Institutes of Health Research ( http://www.cihr-irsc.gc.ca/) operating grant number MOP-126051. MS was supported by a Crohn's and Colitis Foundation of Canada/Canadian Association of Gastroenterology/Canadian Institutes of Health Research fellowship award (CIHR IBD-120966). JR was supported by a Canadian Association of Gastroenterology summer studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Immune Receptors
                Toll-like Receptors
                Immunology
                Immune System
                Innate Immune System
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Campylobacter
                Animal Models of Infection
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Bacterial and Foodborne Illness
                Infectious Diseases
                Bacterial Diseases
                Campylobacteriosis
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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