Title: The role of dendritic cells in T cell immunity to Cryptosporidium This application is for a Mentored Research Scientist Development Award (KO1) on Cryptosporidium, an enteric infection linked with serious human morbidity and mortality worldwide, and against which there is no effective therapy of prevention. Our goal is to elucidate the mechanisms by which immune cells initiate resistance against cryptosporidiosis with a view that a better understanding of the various components of the immune response will lead to development of effective vaccines and adjuvants to combat the infection in humans. Our central hypothesis is that DCs acquire parasite antigens when exposed to Cryptosporidium infection thereby priming specific T cell immunity. We base this on the observations that: 1) intestinal DCs located in the lamina propria directly sample pathogens by protruding dendrites into the gut lumen. DCs in Peyer's patch acquire intestinal antigens transferred by M cells;2) IL-12, which is produced predominantly by dendritic cells, is critical in inducing gamma interferon and controlling C. parvum infection;3) T cells, which can only be primed by dendritic cells, are indispensable in controlling the infection of Cryptosporidium. Based on these observations, the specific aims are designed to provide a comprehensive assessment of the nature of dendritic cell interaction with Cryptosporidium and induction of T cell immunity. They include: 1) Investigate Cryptosporidium antigen uptake by DCs following infection;2) Determine the mode of activation and migration of DCs after exposure to Cryptosporidium infection;3) Investigate dendritic cell-mediated T cell activation in response to Cryptosporidium infection. The proposed studies will provide the basis for understanding the mechanisms for the induction of T cell- mediated anti-Cryptosporidium immunity necessary for future design of vaccines and other methods of interventions.
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