Research

Current Projects by Principal Investigator

Bobby Cherayil, MD

Verena Göbel, MD

Ciarán Kelly, MD

Beth McCormick, PhD

Nanda
Nanthakumar, PhD

David Newburg, PhD

Harry Pothoulakis, MD

Hai Ning Shi, DVM, PhD

W. Allan Walker, MD
Chief

Research
Opportunites

Research

David Newburg, PhD
Associate Professor of Pediatrics

Phone: 617-726-4169
Fax: 617-726-4172
Email: dnewburg@partners.org
Curriculum Vita
Fellows: Nathan Bao, Alix Dubert-Ferrandon

My research is focused on the bioactive glycans of human milk, glycan expression on the intestinal mucosa, and how they function in innate immunity. The emphasis has been on pathogen binding to cell surface glycans of the intestinal mucosa that are targets for common enteropathogens of infants and children, and more specifically on human milk glycans that inhibit this essential first step in pathogenesis. We discovered a series of human milk glycans that inhibit specific pathogens: The human milk glycan that inhibits stable toxin of enterotoxigenic E. coli in vivo is a fucosylated oligosaccharide. Enterohemorrhagic E. coli binding to its host receptor is inhibited by a mannosylated glycopeptide. Rotavirus infection is inhibited by a glycoprotein named lactadherin. Binding of gp120 of HIV to CD4 of its target T-4 lymphocytes is inhibited by glycosaminoglycans and by sulfatides. Sulfatides also inhibit recruitment of polymorphonucleocytes by salmonella. Campylobacter pathogenesis requires binding to host cell receptors containing the H-2 fucosylated epitope and is inhibited by human milk oligosaccharides containing the H-2 moiety. Different strains of noroviruses bind to different carbohydrate epitopes; each strain is specifically inhibited by glycans containing such epitopes. This research demonstrated that the mechanism whereby the host is protected from these pathogens is through the inhibition of binding by the pathogen to its human host cell surface glycan receptor.

In the course of pursuing this research, my laboratory devised and validated many novel analytical techniques. For example, using our methods for the quantitative analysis of individual oligosaccharides in human milk led to finding that the expression of the fucosylated oligosaccharides varies over the course of lactation. Also, the pattern of expression varies among individuals, and this variation is linked to the heterogeneous genotypes of fucosyltransferases that underlie the expression of the various Lewis blood group types. This discovery allowed testing the clinical relevance of the milk oligosaccharides.

The expression in milk of high amounts of specific oligosaccharides that we know to inhibit specific pathogens is associated with a significant reduction in the risk of symptoms of infection by the specific pathogen in nursing infants.  Specifically, a significant association was found for high levels of 2¢-fucosyllactose in milk and low risk of campylobacter-associated diarrhea, high levels of lacto-N-difucohexaose-I and low risk of norovirus-associated diarrhea, high expression of 2-linked oligosaccharides and low risk of diarrhea associated with stable toxin-producing E. coli, high levels of total 2-linked fucosyloligosaccharides and lower risk of diarrhea of all causes, and high expression of lactadherin in milk and low risk of rotavirus-associated diarrhea in the nursing infant. Based on these data, I proposed that the glycans of milk constitute an innate immune system in human milk whereby the mother confers potent and clinically important protection to her nursing infant, and this idea has generated widespread interest and acceptance in pediatrics, nutrition, glycobiology, and mucosal immunology communities.

The projects undertaken in my laboratory increasingly involve questions related to the ontogeny of glycans, especially those in the developing gut, and their relationship to the maturing mucosal immune system. Our expertise in glycobiology is being applied toward defining the ontogeny of glycans in the gut that support colonization by mutualist human gut bacteria, isolation of glycan products from probiotic or commensal bacteria that may have antipathogenic activity, and isolating glycans from fungi that may have anti-inflammatory activity in the gut. The laboratory also studies the role of cell surface glycolipids in cellular trafficking and pathogenesis.