The Role of the TNF-alpha Inducing Protein (Tipα) in the Host Immune and Inflammatory Response to Helicobacter pylori Infection

Abstract

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the human stomach leading to the development of chronic gastritis, peptic ulcers and gastric cancer. It is estimated that 50% of the world population is infected with the bacterium and approximately 15-20% of those infected will develop gastric disease. It remains impossible to predict which individuals will develop disease, but it appears that host and environmental factors play a role along with bacterial virulence factors. A greater understanding of H. pylori virulence factors and their role in pathogenesis will help determine why over 80% of infected individuals remain unsymptomatic and healthy. The H. pylori Tumor necrosis factor- alpha (TNFα) inducing protein (Tipα) is a virulence factor shown to induce multiple pro-inflammatory cytokines in addition to TNFα, and is believed to contribute to cancer development. We hypothesize that Tipɑ will have a pro-infammatory effect on the host immune response and stimulate additional pro-inflammatory pathways in gastric epithelial cells that promote inflammation and carcinogenesis. Mouse infections with wild-type Sydney strain (SS1) and a Tipα mutant (Δtipα) suggest that Tipα plays a significant role in promoting inflammation by the upregulation of several pro-inflammatory cytokines such as TNFα, Interferon-gamma (IFNγ), Interleukin 17 (IL-17) and chemokine 1 (Cxcl1/KC) in mice and may play a role in the development of hyperplasia. A group of co-infected mice with a 1:1 mix of wild-type SS1: and Δtipα had comparable cytokine expression and inflammation to the wild-type mice. Three out of ten animals were positive for Δtipα in the co-infected group suggesting Δtipα can be outcompeted during co-infection. Examination of N87 gastric epithelial cells co-cultured with Δtipα showed similar gene expression and pathway analysis to N87 cells co-cultured with wild-type SS1 suggesting redundant mechanisms within the bacteria that induce similar responses to those induced by Tipα. The use of recombinant Tipα (rTipα) co-cultured with gastric epithelial cells shows the induction of pro-inflammatory upstream regulators TNFα, IFNγ, IL-6 and IL-1. Overall, we identified some putitive gene targets of Tipɑ for further exploration in addition to previous pathways known to be affected by H. pylori infection.