Helicobacter infection: pathogenesis

Abstract

Helicobacter pylori remains one of the world's most prevalent bacterial pathogens, often causing gastritis, peptic ulcer disease, gastric mucosa-associated lymphatic tissue lymphoma, or gastric adenocarcinoma. Elucidation of H. pylori virulence mechanisms and characteristics of the host that contribute to pathogenesis will facilitate the development of both pharmacologic and immunologic therapies. The functional status of the outer inflammatory protein A may have predictive value for duodenal ulcer, and host alleles for interleukin-1beta, interleukin-1R, tumor necrosis factor-alpha, and interleukin-10 correlate with increased risk for gastric cancer. H. pylori vacuolating cytotoxin A and cytotoxin-associated gene A protein interact with multiple host proteins, although downstream signaling events need further characterization. It does appear however, that CagA may participate in a negative feedback loop on Src family kinases to prevent further phosphorylation of CagA. Several models, including delayed type hypersensitivity in immune mice, and spontaneous clearance of H. pylori from interleukin-10 and phagocyte oxidase mice, provide evidence that severe inflammation may be sufficient to eradicate H. pylori. The strategies used by H. pylori to avoid the inflammatory response are also becoming clearer. H. pylori remains viable when internalized by epithelial cells, and it remains viable in macrophage phagosomes by inhibiting phagosome maturation. Additionally, H. pylori may regulate the host immune response through activation of dendritic cells and CD25 regulatory T cells, and it may direct immunosuppression of T cells. Helicobacter pylori virulence is accomplished through many mechanisms, including vacuolating cytotoxin A and CagA activities, and may be predicted based on bacterial and host genotypes. Ultimately, H. pylori persistence may depend on its success in downregulating the inflammatory response.