Functional Analysis of thecagPathogenicity Island inHelicobacter pyloriIsolates from Patients with Gastritis, Peptic Ulcer, and Gastric Cancer

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Abstract
Helicobacter pyloriis the causative agent of a variety of gastric diseases, but the clinical relevance of bacterial virulence factors is still controversial. Virulent strains carrying thecagpathogenicity island (cagPAI) are thought to be key players in disease development. Here, we have comparedcagPAI-dependent in vitro responses inH. pyloriisolates obtained from 75 patients with gastritis, peptic ulcer, and gastric cancer (n= 25 in each group). AGS gastric epithelial cells were infected with each strain and assayed for (i) CagA expression, (ii) translocation and tyrosine phosphorylation of CagA, (iii) c-Src inactivation, (iv) cortactin dephosphorylation, (v) induction of actin cytoskeletal rearrangements associated with cell elongation, (vi) induction of cellular motility, and (vii) secretion of interleukin-8. Interestingly, we found high but similar prevalences of all of thesecagPAI-dependent host cell responses (ranging from 56 to 80%) among the various groups of patients. This study revealed CagA proteins with unique features, CagA subspecies of various sizes, and new functional properties for the phenotypic outcomes. We further showed that induction of AGS cell motility and elongation are two independent processes. Our data corroborate epidemiological studies, which indicate a significant association ofcagPAI presence and functionality with histopathological findings in gastritis, peptic ulcer, and gastric cancer patients, thus emphasizing the importance of thecagPAI for the pathogenicity ofH. pylori. Nevertheless, we found no significant association of the specificH. pylori-induced responses with any particular patient group. This may indicate that the determination of disease development is highly complex and involves multiple bacterial and/or host factors.

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