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

Abstract

Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here we identified members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as novel 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 signaling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells, and enhances the release of proinflammatory 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 antibodymediated abrogation of the HopQ function shows. Together, our data imply the HopQ-CEACAM1 interaction as potentially promising novel therapeutic target to combat H. pyloriassociated diseases. Helicobacter pylori (H. pylori) is one of the most prevalent human pathogens, colonizing half of the world's population. Chronic inflammation elicited by this bacterium is the main cause of gastric cancer 1. During co-evolution with it's human host over more than 60.000 years 2 , the bacterium has acquired numerous adaptations for the long-term survival within its unique niche, the stomach. This includes the ability to buffer the extreme acidity of this environment, the interference with cellular signaling pathways, the evasion of the human immune response and a strong adhesive property to host cells 3. Specifically, H. pylori persistence is facilitated by the binding of BabA and SabA adhesins to the human blood group antigen Leb and the sLex antigen, respectively 4-6. However, adhesion to blood group antigens is not universal, is dynamically regulated during the course of infection and can also be turned off 7. We observed that H. pylori was capable of binding to human gastric epithelium of nonsecretors. Therefore, we hypothesized that the bacterium might be able to interact with other cell surface receptors to ensure persistent colonization. We here show that the H. pylori adhesin HopQ specifically interacts with human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). CEACAMs embrace a group of immunoglobulin superfamily-related glycoproteins with a wide tissue distribution. CEACAM1 can be expressed in leukocytes, endothelial and epithelial cells, CEACAM3 and CEACAM8 in granulocytes, CEACAM5 and CEACAM7 in epithelial cells and CEACAM6 in epithelia and granulocytes. In epithelial cells, transmembrane anchored CEACAM1 as well as glycosylphosphatidylinositol-linked CEACAM5, CEACAM6 and CEACAM7 localize to the apical membrane 8. CEACAMs modulate diverse cellular functions such as cell adhesion, differentiation,...

Binding of Candida albicans to Human CEACAM1 and CEACAM6 Modulates the Inflammatory Response of Intestinal Epithelial Cells

“…While this finding is in agreement with our recent discovery that the interaction of Helicobacter pylori with CEACAM1 results in CXCL8 release in gastric epithelial cells (14), it is in contrast to studies describing inhibitory functions of CEACAM1 in human pulmonary epithelial cells, where ligation of CEACAM1 by M. catarrhalis and N. meningitidis leads to a reduced immune response to TLR2 agonists, resulting in the attenuation of inflammatory responses and allowing for immunoevasion strategies (19, 21). Taken together, these studies indicate that CEACAM1 belongs to a small group of ITIM-bearing immune receptors that can induce both pro- and anti-inflammatory signaling (34).…”

“…CEACAM1, CEACAM5, and CEACAM6 are receptors for a variety of bacterial pathogens and mediate adhesion and internalization—e.g., of Neisseria gonorrhoeae , Neisseria meningitidis , different Escherichia coli strains, Moraxella catarrhalis , Haemophilus influenzae , Salmonella species, and Helicobacter pylori (11, 14). Many of these bacteria have evolved different, structurally unrelated surface proteins that all target the human-specific extracellular immunoglobulin V (IgV)-like amino-terminal domain of CEACAMs (11).…”

Helicobacter pylori Outer Membrane Protein-Related Pathogenesis

“…Based on the crystal structure of the extracellular domain of HopQ, a β-hairpin insertion in the extracellular 3 + 4 helix bundle domain of HopQ is important for CEACAM binding, and this determines the type of HopQ allele. A peptide derived from this domain competitively inhibits HopQ-mediated Cag translocation, similar to that observed with genetic or antibody-mediated abrogation of HopQ function [53,54]. This suggests the possibility that CagA translocation is mediated not only by the T4SS, but also by membrane proteins (Figure 1).…”

Type IV Secretion and Signal Transduction of Helicobacter pylori CagA through Interactions with Host Cell Receptors

“…Once this initial contact of the T4SS pilus is established, CagA appears at the pilus tip as indicated by immunogold labelling, suggesting that CagA could be transported through this appendage [24]. In addition, HopQ-mediated interaction with CEACAM receptors [29,30] and cholesterol in lipid rafts [31] have a function in CagA delivery, but their exact role is not yet clear. Upon translocation, CagA is sequentially phosphorylated (CagA PY ) at EPIYA (Glu-Pro-Ile-Tyr-Ala) sequence repeats [32,33] by the concerted action of Src and Abl tyrosine kinases [34,35,36,37,38].…”