Helicobacter pylori are Gram-negative bacteria that persistently colonize the human gastric mucosa despite the recruitment of immune cells. The H. pylori vacuolating cytotoxin (VacA) recently has been shown to inhibit stimulation-induced proliferation of primary human CD4+ T cells. In this study, we investigated effects of VacA on the proliferation of various other types of primary human immune cells. Intoxication of PBMC with VacA inhibited the stimulation-induced proliferation of CD4+ T cells, CD8+ T cells, and B cells. VacA also inhibited the proliferation of purified primary human CD4+ T cells that were stimulated by dendritic cells. VacA inhibited both T cell-induced and PMA/anti-IgM-induced proliferation of purified B cells. Intoxication with VacA did not alter the magnitude of calcium flux that occurred upon stimulation of CD4+ T cells or B cells, indicating that VacA does not alter early signaling events required for activation and proliferation. VacA reduced the mitochondrial membrane potential of CD4+ T cells, but did not reduce the mitochondrial membrane potential of B cells. We propose that the immunomodulatory actions of VacA on T and B lymphocytes, the major effectors of the adaptive immune response, may contribute to the ability of H. pylori to establish a persistent infection in the human gastric mucosa.

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Helicobacter pylori genomes contain about 30 hop genes that encode outer membrane proteins. H. pylori hopQ alleles exhibit a high level of genetic diversity, and two families of hopQ alleles have been described. Type I hopQ alleles are found more commonly in cag-positive H. pylori strains from patients with peptic ulcer disease than in cag-negative strains from patients without ulcer disease. In this study, we mutated hopQ in four H. pylori strains that each contained a type I hopQ allele, and then analyzed interactions of the wild-type and hopQ mutant strains with AGS cells. In comparison to the wild-type strains, two of the hopQ mutant strains exhibited increased adherence to AGS cells and two hopQ mutants did not exhibit any detectable differences in adherence. Higher levels of tyrosine-phosphorylated CagA were detected when AGS cells were co-cultured with a hyper-adherent hopQ mutant strain than when co-cultured with the corresponding wild-type strain. These data indicate that in some strains of H. pylori, the HopQ protein can attenuate bacterial adherence to gastric epithelial cells.

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