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Respiratory Heterogeneity Shapes Biofilm Formation and Host Colonization in Uropathogenic Escherichia coli

dc.contributor.authorBeebout, Connor J.
dc.contributor.authorEberly, Allison R.
dc.contributor.authorWerby, Sabrina H.
dc.contributor.authorReasoner, Seth A.
dc.contributor.authorBrannon, John R.
dc.contributor.authorDe, Shuvro
dc.contributor.authorFitzgerald, Madison J.
dc.contributor.authorHuggins, Marissa M.
dc.contributor.authorClayton, Douglass B.
dc.contributor.authorCegelski, Lynette
dc.contributor.authorHadjifrangiskou, Maria
dc.identifier.citationAltobelli A, Bauer M, Velez K, Cover TL, Müller A. 2019. Helicobacter pylori VacA targets myeloid cells in the gastric lamina propria to promote peripherally induced regulatory T-cell differentiation and persistent infection. mBio 10:e00261-19. .00261-19.en_US
dc.description.abstractThe gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori-specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3(+)) regulatory T cells that are neuropilin negative and express ROR gamma t. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-beta expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites. IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.en_US
dc.description.sponsorshipThis work was supported by Swiss National Science Foundation (SNF) Temporary Backup Schemes Consolidator Grant BSCGIO_157841/1 to A.M. and by the clinical research priority program on Human Hemato-Lymphatic Diseases, University of Zurich. T.L.C. was supported by NIH grants AI039657 and CA116087 and the Department of Veterans Affairs.en_US
dc.subjectT-cell immunityen_US
dc.subjectT cellsen_US
dc.subjectdendritic cellsen_US
dc.subjecthost-cell interactionsen_US
dc.subjectmucosal infectionen_US
dc.subjectregulatory T cellsen_US
dc.titleRespiratory Heterogeneity Shapes Biofilm Formation and Host Colonization in Uropathogenic Escherichia colien_US
dc.source.collectionThis is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. You are not required to obtain permission to reuse this article.

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