New Insights into the Regulation of the Innate Immune Response During Gastrointestinal Infection and Inflammation

Abstract

The root of many gastrointestinal diseases is a dysregulated immune response. Within the gut, the immune system is constantly active and crucial to maintaining homeostasis and intercepting potential pathogens. In this thesis, I identify regulators of the innate immune response that contribute to gastrointestinal disease progression. Helicobacter pylori is a highly prolific bacterial pathogen that is the greatest risk factor for the development of gastric cancer. The chronic inflammation caused by H. pylori is a result of an overzealous but ineffective immune response and methods to limit this response are needed. Cystathionine γ-lyase (CTH) is part of the mammalian reverse transsulfuration pathway that produces cysteine de novo. I demonstrate that CTH is induced in gastric macrophages during H. pylori infection and is essential for macrophage activation and function. Genetic deletion of CTH resulted in protection from H. pylori-induced gastritis, thus, I propose CTH as a potential therapeutic target that merits further research. Additionally, I demonstrate a cell-specific role of the actin-binding protein talin-1 during pathogen-induced colitis. C. rodentium is the gold standard mouse model for attaching and effacing (A/E) lesion producing enteropathogenic E. coli. Using cell-specific genetic knockout mice, I show that myeloid talin-1 plays a role in the presence of macrophages within the colonic tissues while epithelial talin-1 contributes to the containment of C. rodentium to the luminal surface and the T cell response. Overall, this dissertation provides new insights into the innate immune response of the gastrointestinal tract and proposes potential regulators of macrophage trafficking and function in addition to bacterial colonization.