The role of Th17 cytokines in H.pylori infection

Veterans Health Administration, Decatur PA

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Abstract

DESCRIPTION (provided by applicant): The immune response to Helicobacter pylori is ineffective in clearing infection, but in most cases it successfully restricts bacterial proliferation, and most H. pylori-infected persons remain asymptomatic. A T helper 17 response to H. pylori is required for control of infection, but also controls inflammation and immune cell migration. Our own studies have identified IL-17 signaling as an essential regulator of the host response to H. pylori and a strong candidate for a link between T cell activity and effector functions. The mechanisms by which IL-17 regulates bacterial- host interactions are not completely understood. Addressing the role of T helper 17 cytokines, including IL-17A, IL-17F, and IL-22, during H. pylori infection is particularly interesting because H. pylori is a persistent infection which can lead to adverse outcomes including peptic ulcers and gastric cancer. It is well accepted that IL-17 induces chemokine expression in epithelial cells for the recruitment of neutrophils, but since the receptor for IL-17, IL-17RA, is expressed on many cell types, including epithelial cells, granulocytes, and lymphocytes, its effects are even more widespread. The specific aims are designed to elucidate the relative contributions of cytokines produced by Th17 cells to the epithelial cell and neutrophil response and specifically in control of H. pylori infection and gastritis. We will (1) investigate the role of IL-17 and IL-22 cytokines in stimulating gastric epithelial cell expression of antimicrobial products during H. pylori infection. Moreover, we will (2) determine the role of IL-22 in control of bacterial colonization and maintenance of barrier function during H. pylori infection, and (3) determine whether IL-17 has a direct effect on neutrophil activation during H. pylori infection. In addition to enhancing our understanding of H. pylori infection, these experiments will contribute to our understanding of the immune pathology associated with mucosal infections and immune- mediated diseases, such as psoriasis, inflammatory bowel disease, and rheumatoid arthritis.