Project 2

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Human giardiasis, caused by the protozoan parasite Giardia duodenalis, is one of the most prevalent enteric parasitic protozoan infections globally, with prevalence rates ranging from 2-5% in the developed world and 20- 30% in the developing countries. Human infections are initiated by the ingestion of quadrinucleate cysts along with contaminated food or water and the vegetative forms of the parasite or trophozoites colonize the proximal portions of the small intestine, especially the duodenum and jejunum. Symptomatic infections in humans are characterized by gastrointestinal symptoms that may include abdominal cramps, flatulence, diarrhea, nausea, with a malabsorption syndrome occurring in clinical and subclinical cases and may result in failure to thrive and/or stunted growth, especially in children. Most cases of human giardiasis are self-limiting and are resolved spontaneously within weeks following exposure in immunocompetent individuals, indicating the development of an effective anti-Giardia immunity sufficient for the clearance of G. duodenalis infections in humans. We have found non-redundant functions for chemokine/chemokine receptor signaling pathways in major intestinal sub- compartments as well as across the entire intestinal tract. Consistent with the microenvironmental differences between the small intestine and the colon, the differential expression of bile acids (BAs), as the end-products of cholesterol catabolism, represents one of the major microenvironmental cues shaping intestinal homeostasis and inflammation in these two main anatomical sub-compartments. Using a mouse model of human giardiasis, we will investigate the roles played by the BA in the compartmentalized immune responses along the intestinal tract. Successful completion of these studies will improve our understanding of the mechanisms by which immune cells are imprinted and homed to the intestinal sub-compartments and will further provide insights into the development of novel preventive and therapeutic targets in the context of infections and non-infectious (i.e. IBD, celiac disease) settings in humans.