EPITHELIAL SECRETORY MECHANISMS IN ENTERIC INFECTION

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The long-term goal of the investigator is to improve the understanding and treatment of diarrheal diseases associated with enteric infections. In the context of the Program Project, the goal of the studies proposed in this unit is to provide a functional correlate for host-pathogen interactions defined by other participating investigators. The studies proposed here will focus on two clinically-important enteric pathogens, Salmonella and Giardia, as prototypes of invasive and luminal pathogens, respectively. The overall hypothesis to be tested is that diarrheal illness resulting from infections with these pathogens reflects specific dysfunction of epithelial secretory, absorptive and/or barrier functions, mediated via both direct effects on the epithelium as well as via secondary cell types and mediators. Further, these effects are proposed to involve alterations in either the expression, localization and/or function of key transport and regulatory proteins in the epithelial cells. All studies will be conducted using human-derived model systems given that substantial species differences are known to exist in the development of diarrheal illness in response to infection. Studies will be performed using both reductionist cell line models as well as in xenografts of human intestinal tissue maintained in SCID mice. These latter xenografts, which develop the mature characteristics of pediatric intestine, allow parameters of epithelial function to be assessed in an integrated system. Thus, contributions of non-epithelial cell types to pathology induced by infection can be assessed. They will also allow the study of small intestinal functions, for which adequate cell line models do not exist. Four specific aims are proposed. We will study the effect of infection and pathogenetic mechanisms of changes in (1) chloride secretion, (2) sodium-coupled glucose absorption, (3) brush border disaccharide hydrolysis, and (4) barrier function to small and macro-molecules. The studies will encompass electrophysiological, biochemical and molecular approaches and will be facilitated by the availability of various mutant strains of salmonella. In total, the studies should define paradigms for pathogen-induced intestinal dysfunction. The findings from these studies are accordingly expected to have both basic and clinical implications for our understanding of the intestinal epithelium.