H. pylori interactions with epithelial cells highlighting the roles of adhesins and the type-IV secretion system (T4SS) encoded by cag PAI. (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. cag PAI 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 . 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 . 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 . 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 . 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).