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      Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs.

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          Abstract

          Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here, we identify members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1-mediated signalling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells and enhances the release of pro-inflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a β-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibody-mediated abrogation of the HopQ function shows. Together, our data suggest the HopQ-CEACAM1 interaction to be a potentially promising novel therapeutic target to combat H. pylori-associated diseases.

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          Most cited references34

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          The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues.

          The human CEA family has been fully characterized. It comprises 29 genes of which 18 are expressed; 7 belonging to the CEA subgroup and 11 to the pregnancy specific glycoprotein subgroup. CEA is an important tumor marker for colorectal and some other carcinomas. The CEA subgroup members are cell membrane associated and show a complex expression pattern in normal and cancerous tissues with notably CEA showing a selective epithelial expression. Several CEA subgroup members possess cell adhesion properties and the primordial member, biliary glycoprotein, seems to function in signal transduction or regulation of signal transduction possibly in association with other CEA sub-family members. A modified ITAM/ITIM motif is identified in the cytoplasmatic domain of BGP. A role of CEA in innate immunity is envisioned. Copyright 1999 Academic Press.
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            Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation.

            Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid-binding adhesin (SabA) was isolated with the "retagging" method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection.
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              Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging.

              The bacterium Helicobacter pylori is the causative agent for peptic ulcer disease. Bacterial adherence to the human gastric epithelial lining is mediated by the fucosylated Lewis b (Leb) histo-blood group antigen. The Leb-binding adhesin, BabA, was purified by receptor activity-directed affinity tagging. The bacterial Leb-binding phenotype was associated with the presence of the cag pathogenicity island among clinical isolates of H. pylori. A vaccine strategy based on the BabA adhesin might serve as a means to target the virulent type I strains of H. pylori.
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                Author and article information

                Journal
                Nat Microbiol
                Nature microbiology
                Springer Nature
                2058-5276
                2058-5276
                Oct 17 2016
                : 2
                Affiliations
                [1 ] Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.
                [2 ] German Center for Infection Research, Partner Site Munich, 81675 Munich, Germany.
                [3 ] Imevax GmbH, 81675 Munich, Germany.
                [4 ] Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium.
                [5 ] Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
                [6 ] Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen, 91058 Erlangen, Germany.
                [7 ] Department Chemie, Center for Integrated Protein Science Munich, Institute of Advanced Studies, Technische Universität München, 85747 Garching, Germany.
                [8 ] School of Cellular &Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
                [9 ] Department of Bacteriology, Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, D-80336 Munich, Germany.
                [10 ] Lehrstuhl für Zellbiologie, Universität Konstanz, 78457 Konstanz, Germany.
                [11 ] Department of Pathology, Sumy State University, Sumy 40000, Ukraine.
                [12 ] Septomics Research Centre, Jena University Hospital, 07745 Jena, Germany.
                [13 ] Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07747 Jena, Germany.
                [14 ] Medical Faculty, Institute of Anatomy, University Duisburg-Essen, 45122 Essen, Germany.
                [15 ] Department of Medical Biosciences, Pathology, Umeå University, SE-901 85 Umeå, Sweden.
                Article
                nmicrobiol2016189
                10.1038/nmicrobiol.2016.189
                27748768
                c18d609c-2486-43dd-a383-ed5d22e91614
                History

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