The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea
| العنوان: | The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea |
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| المؤلفون: | Nicolas Tchitchek, Arndt Benecke, Richard A. Strugnell, Christian von Mering, Laurye Van Maele, Wolf-Dietrich Hardt, Jean-Claude Sirard, Kathrin Endt, Andrew J. Macpherson, Mathias Heikenwalder, Baerbel Stecher, Emma Slack, Samuel Chaffron, Andreas J. Mueller |
| المساهمون: | University of Zurich, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Department Klinische Forschung, Gastroenterology Inselspital, Institut des Hautes Études Scientifiques (IHES), IHES, Interactions cellulaires et moléculaires des bactéries pathogènes avec l'hôte, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institute of Neuropathology, University hospital of Zurich [Zurich], Department of Microbiology and Immunology, University of Melbourne, Swiss National Science Foundation (310000-113623/1, to WDH), the Promedica Foundation (1097/A to WDH), the European Union (SavinMucoPath No. 032296, to WDH and JCS), the Agence Nationale de la Recherche (ISPA, 07-PHYSIO-013-02, to AB) and the Ge´nopole Evry (to AB)., European Project, Université de Lausanne (UNIL), Institut des Hautes Etudes Scientifiques (IHES), Sirard, Jean-Claude, SavinMucoPath No. 032296 - INCOMING |
| المصدر: | PLoS Pathogens PLoS Pathogens, 2010, 6 (9), pp.e1001097. ⟨10.1371/journal.ppat.1001097⟩ PLoS Pathogens, Public Library of Science, 2010, 6 (9), pp.e1001097. ⟨10.1371/journal.ppat.1001097⟩ PLoS pathogens PLoS Pathogens, 6 (9) PLoS Pathogens, Vol 6, Iss 9, p e1001097 (2010) |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Immunoglobulin A, Male, Salmonella typhimurium, Infectious Diseases/Gastrointestinal Infections, 2405 Parasitology, Fluorescent Antibody Technique, Gut flora, Immunoenzyme Techniques, Infectious Diseases/Bacterial Infections, Mice, fluids and secretions, Intestinal mucosa, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Biology (General), Intestinal Mucosa, Pathogen, Oligonucleotide Array Sequence Analysis, Mice, Knockout, 0303 health sciences, biology, 2404 Microbiology, O Antigens, Flow Cytometry, 10124 Institute of Molecular Life Sciences, 3. Good health, Microbiology/Immunity to Infections, Diarrhea, Genes, T-Cell Receptor beta, Salmonella Infections, Streptomycin, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Research Article, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Immunology, Blotting, Western, 10208 Institute of Neuropathology, 610 Medicine & health, Colonisation resistance, Microbiology, digestive system, 03 medical and health sciences, Immune system, 1311 Genetics, Virology, Immunology/Immunity to Infections, Genetics, medicine, 1312 Molecular Biology, Animals, Humans, Microbiome, Molecular Biology, 030304 developmental biology, 2403 Immunology, 030306 microbiology, Gene Expression Profiling, RC581-607, biology.organism_classification, Mice, Inbred C57BL, Immunoglobulin A, Secretory, Immunology/Immune Response, biology.protein, 2406 Virology, Metagenome, 570 Life sciences, Parasitology, Immunologic diseases. Allergy, U7 Systems Biology / Functional Genomics, Biomarkers |
| الوصف: | Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA) and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in humans world-wide. S. typhimurium (S. tm att, sseD) causes a self-limiting gut infection in streptomycin-treated mice. After 40 days, all animals had overcome the disease, developed a sIgA response, and most had cleared the pathogen from the gut lumen. sIgA limited pathogen access to the mucosal surface and protected from gut inflammation in challenge infections. This protection was O-antigen specific, as demonstrated with pathogens lacking the S. typhimurium O-antigen (wbaP, S. enteritidis) and sIgA-deficient mice (TCRβ−/−δ−/−, JH −/−, IgA−/−, pIgR−/−). Surprisingly, sIgA-deficiency did not affect the kinetics of pathogen clearance from the gut lumen. Instead, this was mediated by the microbiota. This was confirmed using ‘L-mice’ which harbor a low complexity gut flora, lack colonization resistance and develop a normal sIgA response, but fail to clear S. tm att from the gut lumen. In these mice, pathogen clearance was achieved by transferring a normal complex microbiota. Thus, besides colonization resistance ( = pathogen blockage by an intact microbiota), the microbiota mediates a second, novel protective function, i.e. pathogen clearance. Here, the normal microbiota re-grows from a state of depletion and disturbed composition and gradually clears even very high pathogen loads from the gut lumen, a site inaccessible to most “classical” immune effector mechanisms. In conclusion, sIgA and microbiota serve complementary protective functions. The microbiota confers colonization resistance and mediates pathogen clearance in primary infections, while sIgA protects from disease if the host re-encounters the same pathogen. This has implications for curing S. typhimurium diarrhea and for preventing transmission. Author Summary Numerous pathogens infect the gut. Protection against these infections is mediated by mucosal immune defenses including secreted IgA as well as by the competing intestinal microbiota. However, so far the relative importance of these two different defense mechanisms remains unclear. We addressed this question using the example of non-typhoidal Salmonella (NTS) gut infections which can be spread in stool of infected patients over long periods of time. We used a mouse model to reveal that the intestinal microbiota and the adaptive immune system hold different but complementary functions in fighting NTS infections. A primary Salmonella infection disrupts the normal microbiota and elicits Salmonella-specific sIgA. sIgA prevents disease when the animal is infected with NTS for a second time. However, sIgA was dispensable for pathogen clearance from the gut. Instead, this was mediated by the microbiota. By re-establishing its normal density and composition, the microbiota was necessary and sufficient for terminating long-term fecal Salmonella excretion. This establishes a novel paradigm: The microbiota clears the pathogen from the gut lumen, while sIgA protects from disease upon re-infection with the same pathogen. This has implications for the evolutionary role of sIgA responses as well as for developing microbiota-based therapies for curing infected patients. |
| وصف الملف: | 20844578.pdf - application/pdf; application/pdf; application/application/pdf |
| اللغة: | English |
| تدمد: | 1553-7366 1553-7374 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1d38021bbe5df326d0d653c40d75ca7aTest https://doi.org/10.5167/uzh-35945Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1d38021bbe5df326d0d653c40d75ca7a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537366 15537374 |
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