Epithelial Glycoconjugates as Barriers Against Enteric Infections

Enteric infections remain a leading cause of morbidity and mortality in children under the age of five. Pathogens affecting this age group commonly use lectin-like adhesins to adhere to host glycoproteins and glycolipids expressed on small intestinal enterocytes and/or M cells. The expression patterns of these glycoconjugates can thus impact the host's underlying susceptibility to infection. <P> A variety of factors including age, hormones, diet, and colonization with specific commensal microflora impacts epithelial glycoconjugate expression. We have shown that colonization of adult germ-free (gnotobiotic) with the commensal Bacteroides thetaiotaomicron induces a mature pattern by up-regulating enterocyte-specific expression of a 1,2 fucosyltransferase. Fucosyltransferases link fucose to terminal galactose and N-acetyl-glucosamine residues, and thereby mask potential ligands on epithelial surfaces. <P> These data suggest that colonization with select commensals could be used to therapeutically stimulate beneficial changes in epithelial glycoconjugate expression in susceptible populations. <P> This proposal will test the hypothesis that select microflora, notably B. thetaiotaomicron, stimulate the development of glycoconjugates on the apical surfaces of enterocytes and M cells that reduces the capacity of pathogenic bacteria, viruses and/or toxins to infect/intoxicate the intestinal epithelium. <P> Aims 1 and 2 will determine the full impact of B. thetaiotaomicron on expression and accessibility of epithelial glycoconjugates in the small and large intestines. These aims are directly responsive to RFA HD 08-004 Surveying glycoconjugates on the surface of enterocytes to discover oligosaccharides that may serves as ligands for pathogenic and non-pathogenic bacteria. Aim 3 will specifically test the proposed hypothesis using well-established mouse models of cholera toxin, ricin toxin, reovirus and Salmonella typhimurium infection.