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NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent, TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium
Infections, microbe sampling and occasional leakage of commensal microbiota and their products across the intestinal epithelial cell layer represent a permanent challenge to the intestinal immune system. The production of reactive oxygen species by NADPH oxidase is thought to be a key element of def...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797104/ https://www.ncbi.nlm.nih.gov/pubmed/24143212 http://dx.doi.org/10.1371/journal.pone.0077204 |
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author | Felmy, Boas Songhet, Pascal Slack, Emma Marie Caroline Müller, Andreas J. Kremer, Marcus Van Maele, Laurye Cayet, Delphine Heikenwalder, Mathias Sirard, Jean-Claude Hardt, Wolf-Dietrich |
author_facet | Felmy, Boas Songhet, Pascal Slack, Emma Marie Caroline Müller, Andreas J. Kremer, Marcus Van Maele, Laurye Cayet, Delphine Heikenwalder, Mathias Sirard, Jean-Claude Hardt, Wolf-Dietrich |
author_sort | Felmy, Boas |
collection | PubMed |
description | Infections, microbe sampling and occasional leakage of commensal microbiota and their products across the intestinal epithelial cell layer represent a permanent challenge to the intestinal immune system. The production of reactive oxygen species by NADPH oxidase is thought to be a key element of defense. Patients suffering from chronic granulomatous disease are deficient in one of the subunits of NADPH oxidase. They display a high incidence of Crohn’s disease-like intestinal inflammation and are hyper-susceptible to infection with fungi and bacteria, including a 10-fold increased risk of Salmonellosis. It is not completely understood which steps of the infection process are affected by the NADPH oxidase deficiency. We employed a mouse model for Salmonella diarrhea to study how NADPH oxidase deficiency (Cybb (−/−)) affects microbe handling by the large intestinal mucosa. In this animal model, wild type S. Typhimurium causes pronounced enteropathy in wild type mice. In contrast, an avirulent S. Typhimurium mutant (S.Tm(avir); invGsseD), which lacks virulence factors boosting trans-epithelial penetration and growth in the lamina propria, cannot cause enteropathy in wild type mice. We found that Cybb (−/−) mice are efficiently infected by S.Tm(avir) and develop enteropathy by day 4 post infection. Cell depletion experiments and infections in Cybb (−/−) Myd88 (−/−) mice indicated that the S.Tm(avir)-inflicted disease in Cybb (−/−) mice hinges on CD11c(+)CX(3)CR1(+) monocytic phagocytes mediating colonization of the cecal lamina propria and on Myd88-dependent proinflammatory immune responses. Interestingly, in mixed bone marrow chimeras a partial reconstitution of Cybb-proficiency in the bone marrow derived compartment was sufficient to ameliorate disease severity. Our data indicate that NADPH oxidase expression is of key importance for restricting the growth of S.Tm(avir) in the mucosal lamina propria. This provides important insights into microbe handling by the large intestinal mucosa and the role of NADPH oxidase in maintaining microbe-host mutualism at this exposed body surface. |
format | Online Article Text |
id | pubmed-3797104 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37971042013-10-18 NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent, TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium Felmy, Boas Songhet, Pascal Slack, Emma Marie Caroline Müller, Andreas J. Kremer, Marcus Van Maele, Laurye Cayet, Delphine Heikenwalder, Mathias Sirard, Jean-Claude Hardt, Wolf-Dietrich PLoS One Research Article Infections, microbe sampling and occasional leakage of commensal microbiota and their products across the intestinal epithelial cell layer represent a permanent challenge to the intestinal immune system. The production of reactive oxygen species by NADPH oxidase is thought to be a key element of defense. Patients suffering from chronic granulomatous disease are deficient in one of the subunits of NADPH oxidase. They display a high incidence of Crohn’s disease-like intestinal inflammation and are hyper-susceptible to infection with fungi and bacteria, including a 10-fold increased risk of Salmonellosis. It is not completely understood which steps of the infection process are affected by the NADPH oxidase deficiency. We employed a mouse model for Salmonella diarrhea to study how NADPH oxidase deficiency (Cybb (−/−)) affects microbe handling by the large intestinal mucosa. In this animal model, wild type S. Typhimurium causes pronounced enteropathy in wild type mice. In contrast, an avirulent S. Typhimurium mutant (S.Tm(avir); invGsseD), which lacks virulence factors boosting trans-epithelial penetration and growth in the lamina propria, cannot cause enteropathy in wild type mice. We found that Cybb (−/−) mice are efficiently infected by S.Tm(avir) and develop enteropathy by day 4 post infection. Cell depletion experiments and infections in Cybb (−/−) Myd88 (−/−) mice indicated that the S.Tm(avir)-inflicted disease in Cybb (−/−) mice hinges on CD11c(+)CX(3)CR1(+) monocytic phagocytes mediating colonization of the cecal lamina propria and on Myd88-dependent proinflammatory immune responses. Interestingly, in mixed bone marrow chimeras a partial reconstitution of Cybb-proficiency in the bone marrow derived compartment was sufficient to ameliorate disease severity. Our data indicate that NADPH oxidase expression is of key importance for restricting the growth of S.Tm(avir) in the mucosal lamina propria. This provides important insights into microbe handling by the large intestinal mucosa and the role of NADPH oxidase in maintaining microbe-host mutualism at this exposed body surface. Public Library of Science 2013-10-15 /pmc/articles/PMC3797104/ /pubmed/24143212 http://dx.doi.org/10.1371/journal.pone.0077204 Text en © 2013 Felmy et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Felmy, Boas Songhet, Pascal Slack, Emma Marie Caroline Müller, Andreas J. Kremer, Marcus Van Maele, Laurye Cayet, Delphine Heikenwalder, Mathias Sirard, Jean-Claude Hardt, Wolf-Dietrich NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent, TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium |
title | NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent, TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium |
title_full | NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent, TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium |
title_fullStr | NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent, TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium |
title_full_unstemmed | NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent, TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium |
title_short | NADPH Oxidase Deficient Mice Develop Colitis and Bacteremia upon Infection with Normally Avirulent, TTSS-1- and TTSS-2-Deficient Salmonella Typhimurium |
title_sort | nadph oxidase deficient mice develop colitis and bacteremia upon infection with normally avirulent, ttss-1- and ttss-2-deficient salmonella typhimurium |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797104/ https://www.ncbi.nlm.nih.gov/pubmed/24143212 http://dx.doi.org/10.1371/journal.pone.0077204 |
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