Stomach infection with the bacterium Helicobacter pylori affects billions of people worldwide. The infection, which is usually established during infancy and persists throughout the life of infected individuals, occasionally causes stomach diseases such as chronic gastritis, peptic ulcers and gastric cancers. H. pylori produces two main virulence factors: VacA, a toxin secreted into the extracellular space that enters host cells and causes cellular damage; and CagA, which for unknown reasons is directly injected into the gastric epithelial cells to which the bacteria are attached. H. pylori strains isolated from patients are genetically heterogeneous for these two factors. CagA is often identified in strains isolated from patients with severe gastric disease, and has thus been used as an indicator of virulent strains. Such CagA-positive strains almost always also express a toxic form of VacA, whereas CagA-negative strains usually express a nontoxic form of VacA. The nature of the relationship between these two virulence factors has been a long-standing enigma of H. pylori.

By carrying out genome-wide screening in yeast, as well as experiments in gastric epithelial cells for CagA function, the authors show that CagA specifically inhibits the clathrin-independent pinocytic endocytosis pathway without affecting clathrin-dependent endocytosis. Because VacA enters into host gastric epithelial cells by pinocytic endocytosis, CagA inhibits the entry and function of VacA in the host cells, thereby protecting them from VacA-mediated toxicity. The authors also demonstrate that CagA inhibits the uptake of EGF receptor and RPTPα from the host plasma membrane, which depends, at least in part, on the pinocytic endocytosis pathway.

These data indicate that H. pylori strains that express toxic VacA must co-express CagA to maintain a balance between damage to and protection of the host gastric epithelial cells for their survival, as these cells constitute a crucial environmental niche for H. pylori. This functional antagonism might work as a selective pressure to maintain the evolutionary linkage between CagA and VacA in H. pylori. The capacity of CagA to inhibit endocytosis might also alter host cell signalling pathways, as endocytosis controls the amount of molecules at the plasma membrane and, in turn, the signals transduced by them. Therefore, CagA might contribute to changes in cancer-cell signaling pathways through modifying endocytosis in gastric epithelial cells infected with H. pylori. Understanding the function of CagA and VacA, and the nature of the functional relationship between them, will be essential for obtaining a clear understanding of the gastric diseases caused by H. pylori infection, including cancer.

2010