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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD013021-35
Application #
8514653
Study Section
Special Emphasis Panel (ZHD1-DSR-A)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
35
Fiscal Year
2013
Total Cost
$140,631
Indirect Cost
$25,376
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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; Lawlor, Nathan T; Newburg, David S (2016) Human Milk Components Modulate Toll-Like Receptor-Mediated Inflammation. Adv Nutr 7:102-11
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Newburg, David S; He, Yingying (2015) Neonatal Gut Microbiota and Human Milk Glycans Cooperate to Attenuate Infection and Inflammation. Clin Obstet Gynecol 58:814-26
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Jin, Miao; Tan, Ming; Xia, Ming et al. (2015) Strain-specific interaction of a GII.10 Norovirus with HBGAs. Virology 476:386-94
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
Dai, Ying-Chun; Zhang, Xu-Fu; Xia, Ming et al. (2015) Antigenic Relatedness of Norovirus GII.4 Variants Determined by Human Challenge Sera. PLoS One 10:e0124945
Taft, Diana H; Ambalavanan, Namasivayam; Schibler, Kurt R et al. (2015) Center Variation in Intestinal Microbiota Prior to Late-Onset Sepsis in Preterm Infants. PLoS One 10:e0130604

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