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. 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. These data suggest that colonization with select commensals could be used to therapeutically stimulate beneficial changes in epithelial glycoconjugate expression in susceptible populations. 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.
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 (Item 5) """"""""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.

Public Health Relevance

Infections of the gastrointestinal tract are a leading cause of death in children under the age of five, especially in developing countries. This project aims to develop a new, effective, and inexpensive therapy for administration to newborns that interferes with the ability of disease causing bacteria, viruses, and toxins to adhere to the lining of intestinal tract, and thereby prevent the first steps in the infection process.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD061916-05
Application #
8511759
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (04))
Program Officer
Grave, Gilman D
Project Start
2009-09-15
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$373,283
Indirect Cost
$69,968
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
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Yu, Da-Hai; Gadkari, Manasi; Zhou, Quan et al. (2015) Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome. Genome Biol 16:211
Wang, Sen; Charbonnier, Louis-Marie; Noval Rivas, Magali et al. (2015) MyD88 Adaptor-Dependent Microbial Sensing by Regulatory T Cells Promotes Mucosal Tolerance and Enforces Commensalism. Immunity 43:289-303
Levinson, Kara J; De Jesus, Magdia; Mantis, Nicholas J (2015) Rapid effects of a protective O-polysaccharide-specific monoclonal IgA on Vibrio cholerae agglutination, motility, and surface morphology. Infect Immun 83:1674-83
De Jesus, Magdia; Ostroff, Gary R; Levitz, Stuart M et al. (2014) A population of Langerin-positive dendritic cells in murine Peyer's patches involved in sampling β-glucan microparticles. PLoS One 9:e91002
Ahlawat, Sarita; Xie, Fang; Zhu, Yi et al. (2014) Mice deficient in intestinal epithelium cytochrome P450 reductase are prone to acute toxin-induced mucosal damage. Sci Rep 4:5551

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