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      Helicobacter pylori Type IV Secretion System and Its Adhesin Subunit, CagL, Mediate Potent Inflammatory Responses in Primary Human Endothelial Cells

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          Abstract

          The Gram-negative bacterium, Helicobacter pylori, causes chronic gastritis, peptic ulcers, and gastric cancer in humans. Although the gastric epithelium is the primary site of H. pylori colonization, H. pylori can gain access to deeper tissues. Concurring with this notion, H. pylori has been found in the vicinity of endothelial cells in gastric submucosa. Endothelial cells play crucial roles in innate immune response, wound healing and tumorigenesis. This study examines the molecular mechanisms by which H. pylori interacts with and triggers inflammatory responses in endothelial cells. We observed that H. pylori infection of primary human endothelial cells stimulated secretion of the key inflammatory cytokines, interleukin-6 (IL-6) and interleukin-8 (IL-8). In particular, IL-8, a potent chemokine and angiogenic factor, was secreted by H. pylori-infected endothelial cells to levels ~10- to 20-fold higher than that typically observed in H. pylori-infected gastric epithelial cells. These inflammatory responses were triggered by the H. pylori type IV secretion system (T4SS) and the T4SS-associated adhesin CagL, but not the translocation substrate CagA. Moreover, in contrast to integrin α 5β 1 playing an essential role in IL-8 induction by H. pylori upon infection of gastric epithelial cells, both integrin α 5β 1 and integrin α vβ 3 were dispensable for IL-8 induction in H. pylori-infected endothelial cells. However, epidermal growth factor receptor (EGFR) is crucial for mediating the potent H. pylori-induced IL-8 response in endothelial cells. This study reveals a novel mechanism by which the H. pylori T4SS and its adhesin subunit, CagL, may contribute to H. pylori pathogenesis by stimulating the endothelial innate immune responses, while highlighting EGFR as a potential therapeutic target for controlling H. pylori-induced inflammation.

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          Most cited references43

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          Requirement of vascular integrin alpha v beta 3 for angiogenesis.

          Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin alpha v beta 3 was identified as a marker of angiogenic vascular tissue. Integrin alpha v beta 3 was expressed on blood vessels in human wound granulation tissue but not in normal skin, and it showed a fourfold increase in expression during angiogenesis on the chick chorioallantoic membrane. In the latter assay, a monoclonal antibody to alpha v beta 3 blocked angiogenesis induced by basic fibroblast growth factor, tumor necrosis factor-alpha, and human melanoma fragments but had no effect on preexisting vessels. These findings suggest that alpha v beta 3 may be a useful therapeutic target for diseases characterized by neovascularization.
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            Helicobacter exploits integrin for type IV secretion and kinase activation.

            Integrins are important mammalian receptors involved in normal cellular functions as well as pathogenesis of chronic inflammation and cancer. We propose that integrins are exploited by the gastric pathogen and type-1 carcinogen Helicobacter pylori for injection of the bacterial oncoprotein cytotoxin-associated gene A (CagA) into gastric epithelial cells. Virulent H. pylori express a type-IV secretion pilus that injects CagA into the host cell; CagA then becomes tyrosine-phosphorylated by Src family kinases. However, the identity of the host cell receptor involved in this process has remained unknown. Here we show that the H. pylori CagL protein is a specialized adhesin that is targeted to the pilus surface, where it binds to and activates integrin alpha5beta1 receptor on gastric epithelial cells through an arginine-glycine-aspartate motif. This interaction triggers CagA delivery into target cells as well as activation of focal adhesion kinase and Src. Our findings provide insights into the role of integrins in H.-pylori-induced pathogenesis. CagL may be exploited as a new molecular tool for our further understanding of integrin signalling.
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              Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA.

              Helicobacter pylori translocates the protein CagA into gastric epithelial cells and has been linked to peptic ulcer disease and gastric carcinoma. We show that injected CagA associates with the epithelial tight-junction scaffolding protein ZO-1 and the transmembrane protein junctional adhesion molecule, causing an ectopic assembly of tight-junction components at sites of bacterial attachment, and altering the composition and function of the apical-junctional complex. Long-term CagA delivery to polarized epithelia caused a disruption of the epithelial barrier function and dysplastic alterations in epithelial cell morphology. CagA appears to target H. pylori to host cell intercellular junctions and to disrupt junction-mediated functions.
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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                06 February 2018
                2018
                : 8
                : 22
                Affiliations
                [1] 1Infection & Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Clayton, VIC, Australia
                [2] 2Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Clayton, VIC, Australia
                [3] 3Infection & Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University , Clayton, VIC, Australia
                [4] 4Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research , Clayton, VIC, Australia
                [5] 5Department of Molecular Translational Science, School of Clinical Sciences, Monash University , Clayton, VIC, Australia
                [6] 6Helmholtz Centre for Infection Research, Central Facility for Microscopy , Braunschweig, Germany
                [7] 7Division of Gastroenterology, Vanderbilt University School of Medicine , Nashville, TN, United States
                Author notes

                Edited by: Matthew C. Wolfgang, University of North Carolina at Chapel Hill, United States

                Reviewed by: Lee-Ann H. Allen, University of Iowa, United States; Eric J. Sundberg, Institute of Human Virology, United States

                *Correspondence: Terry Kwok terry.kwok@ 123456monash.edu

                †Present Address: Mona Tafreshi, Illumina Australia Pty Ltd, Scoresby, VIC, Australia

                Jyeswei Guan, Department Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

                Yue Xin, Centenary Institute, Structural Biology Group, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

                Article
                10.3389/fcimb.2018.00022
                5808116
                29468142
                3b5bd072-e99f-4ed9-ad3a-429593de085b
                Copyright © 2018 Tafreshi, Guan, Gorrell, Chew, Xin, Deswaerte, Rohde, Daly, Peek, Jenkins, Davies, and Kwok.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 April 2017
                : 16 January 2018
                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 48, Pages: 15, Words: 10780
                Funding
                Funded by: National Health and Medical Research Council 10.13039/501100000925
                Award ID: APP545983
                Categories
                Microbiology
                Original Research

                Infectious disease & Microbiology
                helicobacter,type iv secretion,interleukin-8,endothelial cells,inflammation,cagl,huvecs

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