There is now strong data supporting our early hypothesis that the reduced incidence of enteric diseases in breastfeeding infants is due, in part, to protection by human milk glycans. Glycans, including glycoproteins, glycolipids, mucins, and glycosaminoglycans, contain complex oligosaccharide structures attached to proteins, lipids, and other molecular backbones. These complex carbohydrate moieties are synthesized by the many glycosyltransferases in the mammary gland;those glycans with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Rotavirus and HIV infections in infants are introduced primarily through oral inoculation, and we discovered that these pathogenic viruses are strongly inhibited by specific high molecular weight human milk glycans in vitro. A subset of the human milk glycosaminoglycans, a chondroitin sulfate, and a component of the human milk sulfated glycosphingolipid fraction each strongly inhibit HIV in solid phase assays and in human leukocytes. A human milk glycoprotein, lactadherin (46 kDa), strongly inhibits rotavirus infection of MA 104 cells, and this molecule accounts for all of the inhibitory activity of human milk against rotaviruses in vitro. This proposal focuses on characterizing these actively antiviral glycans, using state-of-the-art instrumental analytical techniques that have recently become available and can provide detailed understanding of the molecular structure of complex glycan moieties. The molecular mechanisms will be studied to include the inhibition of multiple strains of the pathogens by the whole molecules. This will be followed by research to identify the smallest active moieties of the active molecules, and confirming their mechanism of pathogen inhibition. These studies are designed to culminate in a plan to synthesize the active moieties through genetic engineering of Kluyveromyces lactis, yeast occurring naturally in many dairy products of the human diet, and which has proved amenable to synthesis of other active human milk glycans. The availability of synthetic human milk glycans suitable for oral consumption that inhibit HIV or rotavirus could have large impact on these important threats to public health.
We had found that some human milk components protect infants from disease. A lipid called sulfatide protects human cells against infection by HIV. A large molecule called glycosaminoglycan also inhibits infection of human cells by HIV. Both compounds contain complex sugar structures and contain a sulfate group. A third milk component is a glycoprotein that inhibit cells from being infected by rotavirus, the most common cause of diarrhea in infants. We will study these molecules and find out what part of their structures are protecting against these diseases, so that some day we will be able to manufacture them for people who are not being breast fed, and will encourage all mothers to breastfeed their infants.
|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|
|Hill, David R; Newburg, David S (2015) Clinical applications of bioactive milk components. Nutr Rev 73:463-76|
|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|
|Newburg, David S; Grave, Gilman (2014) Recent advances in human milk glycobiology. Pediatr Res 75:675-9|
|Shang, Jing; Piskarev, Vladimir E; Xia, Ming et al. (2013) Identifying human milk glycans that inhibit norovirus binding using surface plasmon resonance. Glycobiology 23:1491-8|
|Newburg, D S (2013) Glycobiology of human milk. Biochemistry (Mosc) 78:771-85|
|Wiederschain, G Ya (2013) Glycobiology: progress, problems, and perspectives. Biochemistry (Mosc) 78:679-96|
|Liu, Bo; Newburg, David S (2013) Human milk glycoproteins protect infants against human pathogens. Breastfeed Med 8:354-62|
|Nanthakumar, N Nanda; Meng, Di; Newburg, David S (2013) Glucocorticoids and microbiota regulate ontogeny of intestinal fucosyltransferase 2 requisite for gut homeostasis. Glycobiology 23:1131-41|
|Kaplan, Justin M; Shang, Jing; Gobbo, Pierangelo et al. (2013) Conformationally constrained functional peptide monolayers for the controlled display of bioactive carbohydrate ligands. Langmuir 29:8187-92|
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