The Intermediate Region of Helicobacter pylori VacA Is a Determinant of Toxin Potency in a Jurkat T Cell Assay

Abstract

ABSTRACTColonization of the human stomach withHelicobacter pyloriis a risk factor for peptic ulceration, noncardia gastric adenocarcinoma, and gastric lymphoma. The secreted VacA toxin is an importantH. pylorivirulence factor that causes multiple alterations in gastric epithelial cells and T cells. Several families ofvacAalleles have been described, andH. pyloristrains containing certainvacAtypes (s1, i1, and m1) are associated with an increased risk of gastric disease, compared to strains containing othervacAtypes (s2, i2, and m2). Thus far, there has been relatively little study of the role of the VacA intermediate region (i-region) in toxin activity. In this study, we compared the ability of i1 and i2 forms of VacA to cause functional alterations in Jurkat cells. To do this, we manipulated the chromosomalvacAgene in twoH. pyloristrains to introduce alterations in the region encoding the VacA i-region. We did not detect any differences in the capacity of i1 and i2 forms of VacA to cause vacuolation of RK13 cells. In comparison to i1 forms of VacA, i2 forms of VacA had a diminished capacity to inhibit the activation of nuclear factor of activated T cells (NFAT) and suppress interleukin-2 (IL-2) production. Correspondingly, i2 forms of VacA bound to Jurkat cells less avidly than did i1 forms of VacA. These results indicate that the VacA i-region is an important determinant of VacA effects on human T cell function.