Function analysis of Helicobacter pylori cag pathogenicity island

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The diversity of the CagA phosphorylation site, which determines the binding affinity of CagA to SHP-2, is suspected to be an important variable in determining the clinical outcome of Helicobacter pylori infection. In this work, we investigated the diversity of CagA in isolates from two different areas in Japan (Fukui and Okinawa), where gastric cancer risk is different, and examined the relationship between the diversity and clinical outcome. A total of 158 clinical isolates (92 Fukui strains and 66 Okinawa strains) was subjected to sequence analysis of the cagA gene. We also examined the relationship between histological features and diversity of CagA. The CagA phosphorylation and the binding affinity of CagA to SHP-2 were also examined by in vitro infection using human gastric epithelial AGS cells. Almost all (98.9%) Fukui and 68.2% of Okinawa strains possessed East Asian CagA-positive strains. The grades of inflammation, activity of gastritis, and atrophy were significantly higher in gastritis patients infected with the East Asian CagA-positive strain than in gastritis patients infected with cagA-negative or Western CagA-positive strains. Furthermore, all gastric cancer strains were East Asian CagA-positive. Biochemically, the East Asian CagA protein exhibited stronger SHP-2 binding activity than the Western CagA did. These findings suggest that infection of East Asian CagA-positive H. pylori infection is substantially associated with atrophic gastritis and gastric cancer, and that persistent active inflammation induced by the East Asian CagA-positive strain, which possesses stronger SHP-2 binding activity than the Western type, may play a role in the pathogenesis of atrophic gastritis and gastric cancer.