Helicobacter pylori cag pathogenicity island's role in B7-H1 induction and immune evasion.

Taslima T. Lina,Shatha Alzahrani,Irina V. Pinchuk,Yoshio Yamaoka,Arlene H. Sharpe,Victor E. Reyes,Jennifer House,Bill A. Rampy,Rupesh Chaturvedi

doi:10.1371/journal.pone.0121841

Abstract

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 Treg 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 Treg 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 vivo confirmation 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 Treg cells in the stomach, increased IL-10 in the serum. Interestingly, B7-H1-/- mice showed less Treg 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 Treg cell induction; thus, contribute to establishing a persistent infection characteristic of H. pylori.

Highlights

Helicobacter pylori (H. pylori) is a Gram-negative gastroduodenal pathogen
As the H. pylori cag pathogenicity island (PAI) encoded type 4 secretion system (T4SS) is important in delivering bacterial products (i.e., cytotoxin-associated gene A (CagA)) that alter multiple properties of the gastric epithelium, we hypothesized that this virulence factor could influence B7-H1 upregulation
Since our studies with human gastric epithelial cells (GECs) showed involvement of CagA and PG in B7-H1 upregulation, we investigated the role of these components in the upregulation of B7-H1 by murine GECs by infecting Immortomouse stomach epithelium (ImSt) cells with H. pylori PMSS1 strain, which showed significant upregulation of B7-H1 expression by flow cytometry, in parallel with ImSt cells infected with the H. pylori Sydney strain 1 (SS1) strain, whose T4SS is defective [43] and was found to be less effective at increasing of B7-H1 (Fig 5B)

Summary

Introduction

Helicobacter pylori (H. pylori) is a Gram-negative gastroduodenal pathogen. It infects >50% of the world’s population and is linked to chronic gastritis, peptic ulcer disease and gastric cancer (GC) [1,2,3,4,5,6,7]. H. pylori infection usually occurs in childhood and becomes established as a PLOS ONE | DOI:10.1371/journal.pone.0121841. H. pylori T4SS Modulation of B7-H1 and Treg Cells. The University of New Mexico clinical and Translational Science Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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Results

Conclusion