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.).
The authors declare no competing financial interests.
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Königer, V., Holsten, L., Harrison, U. et al. Helicobacter pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA. Nat Microbiol 2, 16188 (2017). https://doi.org/10.1038/nmicrobiol.2016.188
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