Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori

Abstract

Helicobacter pylori is a highly successful pathogen uniquely adapted to colonize humans. Gastric infections with this bacterium can induce pathology ranging from chronic gastritis and peptic ulcers to gastric cancer. More virulent H. pylori isolates harbour numerous well-known adhesins (BabA/B, SabA, AlpA/B, OipA and HopZ) and the cag (cytotoxin-associated genes) pathogenicity island encoding a type IV secretion system (T4SS). The adhesins establish tight bacterial contact with host target cells and the T4SS represents a needle-like pilus device for the delivery of effector proteins into host target cells such as CagA. BabA and SabA bind to blood group antigen and sialylated proteins respectively, and a series of T4SS components including CagI, CagL, CagY and CagA have been shown to target the integrin β1 receptor followed by injection of CagA across the host cell membrane. The interaction of CagA with membrane-anchored phosphatidylserine may also play a role in the delivery process. While substantial progress has been made in our current understanding of many of the above factors, the host cell receptors for OipA, HopZ and AlpA/B during infection are still unknown. Here we review the recent progress in characterizing the interactions of the various adhesins and structural T4SS proteins with host cell factors. The contribution of these interactions to H. pylori colonization and pathogenesis is discussed.

Figure 1

H. pylori interactions with epithelial cells highlighting the roles of adhesins and the type-IV secretion system (T4SS) encoded by cagPAI. (A) (1) H. pylori adhesins mediate apical binding to known and unknown receptors on gastric epithelium and probably also direct signal transduction as indicated. (2) Upregulation of transcription factors such as NF-κB leads to production of pro-inflammatory cytokines and chemokines. (3) Secretion of mediators at basolateral surfaces attracts immune cells to the site of infection. (4) Upon host cell contact, H. pylori assembles T4SS pili at their surface enabling delivery of molecules, CagA and peptidoglycan, from bacterial cytoplasm into host cells. cagPAI proteins (CagA, CagI, CagL and CagY) interact with integrin receptors. Interactions with phosphatidylserine (PS) and cholesterol in lipid rafts are also involved in T4SS processes. T4SS and CagA are involved in numerous cellular effects including disruption of cell-to-cell junctions (5), cytoskeletal rearrangements (6) and nuclear signalling (7). (B) Two models for the assembled T4SS machinery in H. pylori are proposed. Model-1 assumes VirB1-11 proteins, the coupling factor VirD4 and accessory factors such as CagF (a proposed chaperone of CagA) assemble in a similar fashion to that proposed for A. tumefaciens T4SS [10]. Model-2 assumes that the T4SS requires the same VirB/D proteins as model-1 with two major differences. The T4SS pilus surface is covered with CagY (VirB10) molecules and VirB5 is excluded [50]. H. pylori VirB10 is a very large protein (~250 kDa) carrying two transmembrane domains to form a hairpin-loop structure in the pilus as depicted [64]. Immunogold labelling of the loop region in CagY indicated that this is exposed to the extracellular space and is transported to the pilus surface by an unknown mechanism [64]. Abbreviations: AJ (adherens junction); HtrA (High temperature requirement A protease); Leb (Lewis B antigens); MΦ (macrophage); NTP (nucleotide triphosphate); NDP (nucleotide diphosphate); P (phosphate group); SDL (sialyl-dimeric-Lewis × glycosphingolipid); TJ (tight junction).