Article

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

  • Nature Microbiology 2, Article number: 16189 (2016)
  • doi:10.1038/nmicrobiol.2016.189
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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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Acknowledgements

The authors thank J. Koch, J. Lind, B. Maranca-Hüwel and B. Gobs-Hevelke for technical support, C. Konrad and J. Fischer for support with rat experiments and M. Roskrow for discussions and revision of the manuscript. K.M. and H.R. acknowledge use of the Soleil synchrotron, Gif-sur-Yvette, France, under proposal 20,131,370 and support by VIB and the Flanders Science Foundation (FWO) through the Odysseus programme, a postdoctoral fellowship and Hercules funds UABR/09/005. This work was supported by the German Centre for Infection Research, partner site Munich, to M.G., by the BMBF GO-Bio Program to M.G., by the BMBF 01EO1002 to E.K., the Mercator Research Center Ruhr An2012-0070 to B.B.S., the German Science Foundation CRC-796 (B10) and CRC-1181 (A04) to S.B., and the Collaborative Research Center/Transregio 124, Project A5 to H.S.

Author information

Author notes

    • Anahita Javaheri
    • , Tobias Kruse
    • , Kristof Moonens
    • , Han Remaut
    • , Bernhard B. Singer
    •  & Markus Gerhard

    These authors contributed equally to this work.

Affiliations

  1. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany

    • Anahita Javaheri
    • , Raquel Mejías-Luque
    • , Behnam Kalali
    • , Dirk H. Busch
    •  & Markus Gerhard
  2. German Center for Infection Research, Partner Site Munich, 81675 Munich, Germany

    • Anahita Javaheri
    • , Raquel Mejías-Luque
    •  & Markus Gerhard
  3. Imevax GmbH, 81675 Munich, Germany

    • Tobias Kruse
    • , Behnam Kalali
    •  & Markus Gerhard
  4. Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium

    • Kristof Moonens
    • , Ayla Debraekeleer
    •  & Han Remaut
  5. Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium

    • Kristof Moonens
    • , Ayla Debraekeleer
    •  & Han Remaut
  6. Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen, 91058 Erlangen, Germany

    • Carmen I. Asche
    • , Nicole Tegtmeyer
    •  & Steffen Backert
  7. Department Chemie, Center for Integrated Protein Science Munich, Institute of Advanced Studies, Technische Universität München, 85747 Garching, Germany

    • Nina C. Bach
    •  & Stephan A. Sieber
  8. School of Cellular & Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK

    • Darryl J. Hill
  9. Department of Bacteriology, Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, D-80336 Munich, Germany

    • Verena Königer
    •  & Rainer Haas
  10. Lehrstuhl für Zellbiologie, Universität Konstanz, 78457 Konstanz, Germany

    • Christof R. Hauck
  11. Department of Pathology, Sumy State University, Sumy 40000, Ukraine

    • Roman Moskalenko
  12. Septomics Research Centre, Jena University Hospital, 07745 Jena, Germany

    • Esther Klaile
    •  & Hortense Slevogt
  13. Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07747 Jena, Germany

    • Esther Klaile
  14. Medical Faculty, Institute of Anatomy, University Duisburg-Essen, 45122 Essen, Germany

    • Alexej Schmidt
    •  & Bernhard B. Singer
  15. Department of Medical Biosciences, Pathology, Umeå University, SE-901 85 Umeå, Sweden

    • Alexej Schmidt

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Contributions

A.J., T.K., K.M., A.D., C.I.A., N.T., B.K., N.C.B., A.S. and B.B.S. performed the experiments. S.A.S., D.J.H., R.M., B.B.S., R.H., V.K., E.K., H.S. and C.R.H. provided reagents and tools. A.J., B.B.S., H.R., D.H.B., R.M.-L., S.B. and M.G. conceived the experiments, analysed the data and wrote the manuscript. All authors read and approved the final manuscript.

Competing interests

B.K. and T.K. are employees and Shareholders of ImevaX GmbH. M.G., A.J., B.B.S., S.B., H.R., K.M. and T.K. are named as inventors on a patent application related to HopQ. The other authors declare no competing financial interests.

Corresponding author

Correspondence to Markus Gerhard.

Supplementary information

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  1. 1.

    Supplementary information

    Supplementary Figures 1–6, Supplementary Tables 1–3, Original gel images