Cytokine signaling and IEC restitution in enteropathy: the Giardia paradigm

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DESCRIPTION (provided by applicant): This is an application for a Career Development Award (K08) for Luther Bartelt, MD. Dr. Bartelt is an Infectious Disease Fellow at the University of Virginia in the Division of Infectious Diseases and International Health. His research is being conducted under the mentorship of Dr. Richard L. Guerrant, MD, FIDSA, Thomas H. Hunter Professor of International Medicine in Infectious Diseases and International Health at the University of Virginia School of Medicine. Dr. Guerrant is a recipient of the Infectious Disease Society of America Mentor Award, and has mentored more than 150 students and fellows during his career. The proposed project will be executed at the University of Virginia in the newly constructed Carter Harrison Medical Science Building with more than 100,000 net square feet of research space and access to state of the art facilities for animal research and molecular equipment. Dr. Bartelt is pursuing a career as a physician-scientist focusing on enteric infections that contribute to environmental enteropathy, an exceedingly common cause of childhood malnutrition. His immediate goal is to gain expertise in the pathogenesis of the ubiquitous protozoan pathogen G. lamblia as a cause of growth failure. G. lamblia infection occurs in up to 90% of children and in some populations associates with malnutrition. Field investigations of the impact of G. lamblia have reached a state of equipoise, with findings demonstrating protection from acute diarrhea but increased risk of persistent diarrhea. This project will utiliz a novel C57Bl/6 murine model of persistent giardiasis to investigate mechanisms that lead to impaired growth following G. lamblia infection. This work builds on Dr. Bartelt's discovery that the C57Bl/6 strain is susceptible to persistent infection following challenge with G. lamblia H3 purified cysts. It is innovative, as no other investigators have recently published a model of persistent Giardia and malnutrition interactions. Giardia-infected mice develop impaired growth, a phenotype that is accelerated during concomitant malnutrition. The hypothesis tested is that G. lamblia impairs intestinal epithelial cell (IEC) proliferation and differentiation, and that compensatory adaptive host mucosal defenses are necessary for IEC restitution. Preliminary data shows that malnourished-infected mice have blunted villi and diminished crypt proliferation compared to nourished-infected controls. Furthermore, malnourished mice have diminished tissue IL4 and IL5 responses to infection. Collectively, these findings have led to the hypothesis that in this novel murine model of giardiasis and malnutrition, ineffective intestinal epithelial ell (IEC) proliferation leads to growth failure, and that IL4-related host mucosal responses are protective. This project will define early epithelial cell responses to G. lamblia H3 in vivo, inducer signaling molecules in the epithelial compartment during early and established G. lamblia H3 infection, the cellular and mucosal molecular aberrations caused by malnutrition in response to G. lamblia, and will define the role of IL4 for IEC proliferation during early and established giardiasis as compared to alternative cytokine-mediated pathways. The findings will advance knowledge of G. lamblia pathogenesis and mucosal defenses to enteric pathogens that promote enteropathy in general. The outlined career development plan is inclusive of graduate level courses on immunology and cellular biology and complementary laboratory workshops that will enhance both knowledge and technical skills in this field. Furthermore, the career development plan includes a certificate course in Faculty Development, which in combination with the research project will provide a solid foundation for transition to an independent researcher and mentor. Excellent mentorship along with a supportive environment with a well-proven track record will provide experimental expertise and scientific guidance. RELEVANCE: G. lamblia is a globally ubiquitous pathogen that associates with persistent diarrhea and is syndemic with malnutrition. This research will identify mechanisms whereby G. lamblia induces growth failure. The focus will be on the role of host mucosal defenses that facilitate epithelial cell proliferation. The results will be useful for improving strategies for mucosal repair in malnourished children and enteric diseases in general.