Lina Taslima T, Alzahrani Shatha, House Jennifer, Yamaoka Yoshio, Sharpe Arlene H, Rampy Bill A, Pinchuk Irina V, Reyes Victor E
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States Of America.
Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States Of America.
PLoS One. 2015 Mar 25;10(3):e0121841. doi: 10.1371/journal.pone.0121841. eCollection 2015.
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.
在幽门螺杆菌（H. pylori）感染期间，胃固有层中的CD4 + T细胞反应低下，并由Treg细胞控制的Th1/Th17细胞反应极化。我们之前已经表明，幽门螺杆菌上调胃上皮细胞（GEC）上B7-H1的表达，进而抑制T细胞增殖、效应功能，并在体外诱导Treg细胞。在本研究中，我们调查了幽门螺杆菌感染诱导B7-H1的潜在机制及其与慢性感染的功能相关性。使用幽门螺杆菌野生型（WT）、cag致病岛（cag PAI-）和cagA-同基因突变株，我们证明幽门螺杆菌需要其IV型分泌系统（T4SS）以及效应蛋白CagA和肽聚糖（PG）片段来上调GEC上B7-H1的表达。我们的研究还表明，幽门螺杆菌利用p38丝裂原活化蛋白激酶（MAPK）途径上调GEC中B7-H1的表达。当用具有功能性T4SS递送系统的幽门螺杆菌PMSS1菌株感染C57BL/6小鼠，而不是用缺乏功能性T4SS的幽门螺杆菌SS1菌株感染时，在体内得到了证实，这导致胃黏膜中B7-H1表达强烈上调、细菌载量增加、胃中Treg细胞诱导、血清中IL-10增加。有趣的是，B7-H1基因敲除小鼠在感染后显示出较少的Treg细胞和降低的细菌载量。这些研究证明了幽门螺杆菌T4SS组件如何激活p38 MAPK途径、上调GEC上B7-H1的表达并导致Treg细胞诱导；因此，有助于建立幽门螺杆菌特有的持续感染。
