The Human Gastric Pathogen Helicobacter pylori and Its Association with Gastric Cancer and Ulcer Disease
Figure 8
Molecular pathogenesis. H. pylori has evolved different mechanisms to destroy intercellular junctions. (a) The secretion of a bacterial protease leads to the shedding of E-cadherin, an important component of adherence junctions. The toxin CagA, which is translocated in the epithelial cell by the bacterial T4SS, interacts with ZO-1, thereby, destroying the formation of tight junctions. By crossing the intercellular space, H. pylori reaches basolateral integrins which function as T4SS receptors. (b) The T4SS also delivers peptidoglycan into the host cell. Peptidoglycan is recognized by NOD-1 which activates the transcription of proinflammatory genes such as IL8 via the transcription factors NF-κB and AP-1. AP-1 is activated via MAP kinases (MAPK). (c) VacA induces vacuolization as well as mitochondria-mediated apoptosis in epithelial cells, whereas CagA induces drastic morphological changes such as cellular elongation. CagA and VacA counteract each other. (d) The T4SS component CagL mediates the interaction between the T4SS and integrins, thereby leading to the dissociation of the metalloproteinase ADAM17, a process which inhibits the expression of the H+, K+-ATPase. (e) CagA is translocated via phosphatidylserine-rich domains into the host cell where it is phosphorylated via Src kinases and Abl. Phosphorylation leads to an interaction with the tyrosine phosphatase SHP-2 which induces a constant activation of ERK1/2. These events cause cellular elongation. Furthermore, CagA can inhibit EGFR endocytosis thereby blocking receptor degradation. CagA also activates β-catenin and STAT3 which leads to transcription of oncogenes. β-catenin activation can also be CagA independent, induced by an AKT-mediated phosphorylation of the β-catenin inhibitor GSK3β. Interaction between CagA and the PAR1/MARK complex can lead to a depolarization of the host cell.
