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.
The prevalence of H. pylori infection is higher in the Far East, Middle East, and many developing countries than in the United States. Persons from the United States who travel to these parts of the world may acquire H. pylori infection while overseas. Therefore, it seems likely that we may see many new cases of H. pylori infection and an increase in H. pylori-associated illnesses in the United States as Veterans return from sites of conflict in Afghanistan, Iraq, and countries in the Far East such as Korea. Advancement in our understanding of the immune response to H. pylori will broadly impact the health of Veterans by bringing us closer to an effective H. pylori vaccine. Moreover, understanding the role of inflammatory cytokines during the immune response to H. pylori infection in the gastric mucosa should increase our understanding of the immunopathology during immune-mediated diseases such as inflammatory bowel disease and rheumatoid arthritis.
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