Mucosal Responses to Minimally Invasive Pathogens

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Constant exposure to harmless food antigens requires that intestinal immune responses are normally biased towards tolerance and development of regulatory T cells, yet infections with intestinal pathogens induce effector T cells and aggressive antimicrobial immune defenses. The mechanisms underlying the differential recognition of harmless food antigens and threatening microbial antigens, and the corresponding immune decision processes, are central to the understanding of mucosal immunity and its exploitation for preventive and therapeutic medical strategies such as vaccination and immunotherapy. The "reprogramming" from regulatory to effector T cells typically occurs in the context of inflammation initiated by innate recognition of conserved microbial molecules through Toll-like receptors and other innate sensors. However, the host mounts effective immune responses to certain enteric pathogens without mucosal inflammation. An important pathogen of this category is the protozoan parasite, Giardia, which is a major cause of diarrheal disease woridwide. It colonizes the lumen and epithelial surface of the small intestine, and activates effective mucosal immune defenses, but does not invade the mucosa or cause significant inflammation. The overall goal of our studies is to exploit Giardia as a model to elucidate the mechanisms that govern immune decisions in the intestinal tract in the absence of inflammation. The studies have the following Specific Aims: Aim 1. To determine the mechanisms of dendritic cell-dependent immune defense against Giardia. Aim 2. To define the mechanisms of G/ard/a-triggered colitis in suseptible hosts. Aim 3. To investigate the function of IL-17 in giardiasis. The proposed studies will generate important new insights into the immune processes and decisions that take place in the intestinal tract at the interface of local resident cells, innate immune cells, and professional immune cells of the T and B cell lineages in the context of a protozoan infection. Furthermore, the work will provide a basis for the rational design of improved strategies for treating and preventing giardiasis and possibly infection with other clinically important luminal pathogens. RELEVANCE (See instructions): Giardia lamblia, a NIAID/CDC Category B priority pathogen, is a major cause of diarrheal disease woridwide and the leading cause of waterborne disease in the United States. Giardia is highly contagious and a credible threat to public water supplies and health. New insights into immune defenses against the parasite will be important for designing improved treatment and prevention strategies against giardiasis.