Helicobacter pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA

  • Nature Microbiology 2, Article number: 16188 (2016)
  • doi:10.1038/nmicrobiol.2016.188
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Helicobacter pylori (Hp) strains that carry the cag type IV secretion system (cag-T4SS) to inject the cytotoxin-associated antigen A (CagA) into host cells are associated with peptic ulcer disease and gastric adenocarcinoma. CagA translocation by Hp is mediated by β1 integrin interaction of the cag-T4SS. However, other cellular receptors or bacterial outer membrane adhesins essential for this process are unknown. Here, we identify the HopQ protein as a genuine Hp adhesin, exploiting defined members of the carcinoembryonic antigen-related cell adhesion molecule family (CEACAMs) as host cell receptors. HopQ binds the amino-terminal IgV-like domain of human CEACAM1, CEACAM3, CEACAM5 or CEACAM6 proteins, thereby enabling translocation of the major pathogenicity factor CagA into host cells. The HopQ–CEACAM interaction is characterized by a remarkably high affinity (KD from 23 to 268 nM), which is independent of CEACAM glycosylation, identifying CEACAMs as bona fide protein receptors for Hp. Our data suggest that the HopQ–CEACAM interaction contributes to gastric colonization or Hp-induced pathologies, although the precise role and functional consequences of this interaction in vivo remain to be determined.

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The authors acknowledge support from collaborating gastroenterologists who collected gastric biopsies in the framework of the Africa Infectiology Study in Nigeria, especially at Lagos University Teaching Hospital, the University College Hospital (UCH) Ibadan and the University Teaching Hospital Complex Ile-Ife. The authors thank V. Naegele for CEACAM1 and CEACAM5 transfected HEK293 cells, E. Vetter for staining of CEA immunohistology sections, M. Schiemann and L. Henkel for FACS sorting of transfected cells and E. Weiss for technical support. This work was supported by grants from DFG (HA2856/6-2 to C.R.H. and HA2697/16-1, 17-1 and 18-1 and SFB914 Project B05 to R.H.) and in part by an Alexander von Humboldt Foundation Experienced Research Fellowship (to E.J.S.).

Author information

Author notes

    • Verena Königer
    •  & Lea Holsten

    These authors contributed equally to this work.


  1. Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, Pettenkoferstraße 9a, D-80336 München, Germany

    • Verena Königer
    • , Lea Holsten
    • , Ute Harrison
    • , Benjamin Busch
    • , Eva Loell
    • , Qing Zhao
    • , Wolfgang Fischer
    •  & Rainer Haas
  2. Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland 21201, USA

    • Daniel A. Bonsor
    •  & Eric J. Sundberg
  3. Lehrstuhl Zellbiologie, Fachbereich Biologie, Universität Konstanz, D-78457 Konstanz, Germany

    • Alexandra Roth
    • , Arnaud Kengmo-Tchoupa
    •  & Christof R. Hauck
  4. Molecular Biology and Biotechnology Division, Nigerian Institute of Medical Research, 6 Edmond Crescent, Yaba, PMB 2013 Lagos, Nigeria

    • Stella I. Smith
  5. Institut für Pathologie, Ludwig-Maximilians-Universität, D-80337 München, Germany

    • Susanna Mueller
  6. Department of Medicine, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland 21201, USA

    • Eric J. Sundberg
  7. Department of Microbiology and Immunology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland 21201, USA

    • Eric J. Sundberg
  8. Tumor Immunology Laboratory, LIFE Center, Ludwig-Maximilians-Universität, Feodor-Lynen-Str. 19, D-81377 München, Germany

    • Wolfgang Zimmermann
  9. Department of Urology, University Hospital, Ludwig-Maximilians-Universität, Marchioninistr. 15, D-81377 München, Germany

    • Wolfgang Zimmermann
  10. German Center for Infection Research (DZIF), partner site LMU München, Germany

    • Rainer Haas


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V.K. carried out Hp mutant generation, pulldown assays and knockdowns. L.H. performed mutant CEACAM construction and Hp binding assays. E.L. carried out microscopy studies with patient material and B.B. carried out microscopy studies with Hp-infected cell lines. D.A.B. investigated the expression of HopQ and CEA-N in E. coli and carried out ITC experiments. U.H. performed in vivo studies and histological experiments. A.R. generated the soluble CEACAM construct. A.K.-T. prepared and purified soluble CEACAM constructs. S.I.S. coordinated biopsies in Lagos. S.M. generated pathology data. E.J.S. analysed the ITC experimental results. W.Z. carried out CEACAM plasmid construction. Q.Z. conducted CEACAM5 luciferase reporter assays. W.F. carried out Hp omp gene analysis and Hp mutant construction. C.R.H. provided CEACAM reagents and CEA-transgenic mice. R.H. designed and coordinated the project and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rainer Haas.

Supplementary information

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  1. 1.

    Supplementary information

    Supplementary Figures 1-10, Supplementary Table 1-4, Original gel images