This project focuses on the role of human milk glycans as pathogen-binding inhibitors that protect against disease caused by two major viral pathogens: the noroviruses (NVs) and the rotaviruses (RVs). In the current grant cycle, we have made significant progress in defining the role of glycans, specifically those identified as histo-blood group antigens (HBGAs), as receptors for NVs. We have described eight receptor binding patterns of NVs according to the ABO, Lewis and secretor types of human HBGAs;the majority of these patterns involve substantial binding to secretor (a1, 2-fucosyl) oligosaccharide or glycoprotein moieties. We have also demonstrated inhibition of major NV strains from binding to their receptors by human milk glycans of secretor mothers (glycans with a1, 2-fucosyloligosaccharide epitopes);these glycans are HBGA analogs, and serve as decoy receptors for various strains of NVs. In this renewal we will test the secretor phenotype as a major biomarker for risk of NV diarrhea in children and the secretor phenotypes of mothers as a biomarker for protection of their breast-fed children against NV disease in our population-based cohorts. We also will examine the variation in risk among secretors with different ABO blood types. Towards development of human milk glycans as potential novel prophylactic or therapeutic agents against NV diarrhea, we will identify and characterize the specific high molecular weight (MW) glycans in human milk that have high affinity/avidity of binding to NVs. For RVs, we will follow the same pathway of investigation as used for NVs: searching for a carbohydrate receptor (fucosyl, sialyl and non-sialyl) for RVs, testing if the carbohydrate epitopes on human milk lactadherin are involved in RV recognition, and examining glycan expression in children and their mothers'milk in associationwith RV infection in children. Finally, we will perform in vitro and pre-clinical studies to design and test synthetic human milk glycan analogs and natural products as potential antivirals against NVs and RVs.
The research proposed in this application is designed to transform our fundamental understanding of human milk glycans and infant glycans in relation to risk of viral causes of diarrhea and to translate our discoveries into new medications, food substances, and diagnostic tools that promote the health and survival of infants and children worldwide.
|Young, Bridget E; Patinkin, Zachary W; Pyle, Laura et al. (2017) Markers of Oxidative Stress in Human Milk do not Differ by Maternal BMI But are Related to Infant Growth Trajectories. Matern Child Health J 21:1367-1376|
|He, YingYing; Lawlor, Nathan T; Newburg, David S (2016) Human Milk Components Modulate Toll-Like Receptor-Mediated Inflammation. Adv Nutr 7:102-11|
|Vanchiere, John A; Carillo, Berenice; Morrow, Ardythe L et al. (2016) Fecal Polyomavirus Excretion in Infancy. J Pediatric Infect Dis Soc 5:210-3|
|Ward, Doyle V; Scholz, Matthias; Zolfo, Moreno et al. (2016) Metagenomic Sequencing with Strain-Level Resolution Implicates Uropathogenic E. coli in Necrotizing Enterocolitis and Mortality in Preterm Infants. Cell Rep 14:2912-24|
|Newburg, David S; Ko, Jae Sung; Leone, Serena et al. (2016) Human Milk Oligosaccharides and Synthetic Galactosyloligosaccharides Contain 3'-, 4-, and 6'-Galactosyllactose and Attenuate Inflammation in Human T84, NCM-460, and H4 Cells and Intestinal Tissue Ex Vivo. J Nutr 146:358-67|
|He, YingYing; Liu, ShuBai; Kling, David E et al. (2016) The human milk oligosaccharide 2'-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut 65:33-46|
|Newburg, David S; Morelli, Lorenzo (2015) Human milk and infant intestinal mucosal glycans guide succession of the neonatal intestinal microbiota. Pediatr Res 77:115-20|
|Currier, Rebecca L; Payne, Daniel C; Staat, Mary A et al. (2015) Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population. Clin Infect Dis 60:1631-8|
|Payne, Daniel C; Currier, Rebecca L; Staat, Mary A et al. (2015) Epidemiologic Association Between FUT2 Secretor Status and Severe Rotavirus Gastroenteritis in Children in the United States. JAMA Pediatr 169:1040-5|
|Hill, David R; Newburg, David S (2015) Clinical applications of bioactive milk components. Nutr Rev 73:463-76|
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