Cytokine signaling and IEC restitution in enteropathy: the Giardia paradigm

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DESCRIPTION (provided by applicant): Giardia lamblia is a ubiquitous intestinal protozoan parasite that one of the most commonly isolated enteric pathogens in children less than 2 years old, reaching up to 90% cumulative incidence in some populations. G. lamblia infections are syndemic with malnutrition, the latter of which is responsible for an estimated 1/3 of childhood deaths and 60% of deaths due to diarrhea. Field studies demonstrate that G. lamblia associates with persistent diarrhea, and in some populations there is correlation with childhood stunting and impaired development. This career development award will use a newly developed C57Bl/6 murine model of persistent giardiasis to investigate mechanisms that lead to impaired growth following G. lamblia infection. Recent work has identified that the C57Bl/6 strain is susceptible t persistent infection following challenge with G. lamblia Assemblage B (H3) purified cysts (Bartelt, et al. JCI, 2013). Infection accentuates malnutrition in protein-energy deficiency, and associates with villus blunting. Furthermore, protein-energy deficiency alters the small intestinal inflammatory response (blunted IL-4 and IL-5 mRNA and relative diminishment of B220+ cells), despite a similar parasite burden. Collectively, these findings have led to the hypothesis that in this novel murine model of giardiasis and malnutrition, G. lamblia -enteropathy leads to growth faltering through intestinal inflammation and impaired epithelial cell homeostasis. This project will evaluate in vivo (C57Bl/6; G. lamblia purified H3 cysts) the resultant nutrient deficiencies i giardiasis (serum free amino acids (HPLC), minerals, and vitamins), the nutritional factors that influence G. lamblia disease (using current interventions for diarrhea and malnutrition), and the important inflammatory mediators and T-cell responses that alter epithelial cell homeostasis and growth in giardiasis. The outlined career development plan in this proposal will enhance the success of this project by combining graduate level course work with technical training and seminars and conferences focusing on mucosal immunology and enteric parasitic infections. Excellent mentorship will provide experimental expertise and scientific guidance creating a successful environment for the development of an independent clinician-scientist.