Journal
PLOS ONE
Volume 10, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0121841
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Funding
- National Institutes of Health [AI68712, DK090090-01, CA127022]
- American Gastroenterological Association Research Scholar Award
- NIH [1U54RR02614]
- University of Texas Medical Branch Clinical and Translational Sciences Award
- Sealy Endowment and Institute for Human Infection and Immunity
- UTMB Sealy Centre for Vaccine Development Pre-doctoral Fellowship
- McLaughlin Pre-doctoral Fellowship
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During Helicobacter pylori (H. pylori) infection CD4(+) T cells in the gastric lamina propria are hyporesponsive and polarized by Th1/Th17 cell responses controlled by T-reg cells. We have previously shown that H. pylori upregulates B7-H1 expression on GEC, which, in turn, suppress T cell proliferation, effector function, and induce T-reg cells in vitro. In this study, we investigated the underlying mechanisms and the functional relevance of B7-H1 induction by H. pylori infection to chronic infection. Using H. pylori wild type (WT), cag pathogenicity island (cag PAI(-)) and cagA(-) isogenic mutant strains we demonstrated that H. pylori requires its type 4 secretion system (T4SS) as well as its effector protein CagA and peptidoglycan (PG) fragments for B7-H1 upregulation on GEC. Our study also showed that H. pylori uses the p38 MAPK pathway to upregulate B7-H1 expression in GEC. In vivoconfirmation was obtained when infection of C57BL/6 mice with H. pylori PMSS1 strain, which has a functional T4SS delivery system, but not with H. pylori SS1 strain lacking a functional T4SS, led to a strong upregulation of B7-H1 expression in the gastric mucosa, increased bacterial load, induction of T-reg cells in the stomach, increased IL-10 in the serum. Interestingly, B7-H1(-/-) mice showed less T-reg cells and reduced bacterial loads after infection. These studies demonstrate how H. pylori T4SS components activate the p38 MAPK pathway, upregulate B7-H1 expression by GEC, and cause T-reg cell induction; thus, contribute to establishing a persistent infection characteristic of H. pylori.
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