Narrative Description of Research
Dr. Newburg’s research experience is on glycobiology of human milk, intestinal mucosa, and brain. His emphasis is on pathogen binding to cell surface glycans of the mucosa of the intestine and lung: identifying glycan targets for common enteropathogens of infants, and glycans, primarily those from human milk, that inhibit binding to these glycan targets. This has lead to additional emphases, including the genetic basis of heterogeneous expression of gut glycans, developmental regulation of intestinal glycans, and interaction between intestinal mucosa and microbiota during colonization of the gut.
In the past, our laboratory has discovered a series of human milk glycans that inhibit specific pathogens: A fucosylated oligosaccharide that inhibits stable toxin of enterotoxigenic E. coli; a mannosylated glycopeptide that inhibits Enterohemorrhagic E. coli binding to its host receptor; a glycoprotein named lactadherin that inhibits Rotavirus infection; glycosaminoglycans and sulfatides that inhibit binding of HIV to CD4, and HIV infection of T-4 lymphocytes; H-2 fucosylated glycans that inhibit Campylobacter pathogenesis; and carbohydrate epitopes that inhibit specific strains of noroviruses. This research includes studies on the mechanisms whereby inhibition of pathogen binding protects the human host cell.
This research required devising and utilizing many novel analytical techniques, including quantitative analysis of individual oligosaccharides in human milk that led to defining population and individual variation of glycan expression in milk, and allowed testing of the clinical relevance of the milk oligosaccharides. For the analysis of glycans, we continue to utilize various chromatographic techniques for isolation of glycans of interest, and state-of-the-art instrumentation for analyses, such as LC/MS and CE-TOF-MS. Our data led to our proposing that glycans constitute an innate immune system in human milk; as such, we believe that they act as the principal first line of defense whereby the mother confers potent and clinically important protection to her nursing infant. This idea has generated widespread interest and acceptance.
Our current activities involve several collaborative research projects, including:
The role of human milk oligosaccharides and other glycans in preventing or ameliorating the symptoms of diarrhea due to bacterial and viral enteric pathogens, with collaborators Morrow and Jiang from Cincinnati Children’s Hospital, and Ruiz-Palacios in Mexico City [P01 HD 013021].
The synthesis of bioactive human milk oligosaccharides to determine their mechanisms of action, with collaborators Jiang, Ruiz-Palacios, Robbins (Boston University) and McCoy (Glycosyn, Medford, MA) [U01 AI 075563].
The mechanism and structure/function relationship of human milk glycans in inhibiting HIV infection and rotavirus infection, with collaborators Costello and Zaia (Boston University), Viveros and Ruiz-Palacios (Mexico), and Ratner (University of Washington) [R01 HD 061930].
The relationship between human genotype for glycosyltransferases, intestinal colonization, and risk of Necrotizing Enterocolitis (NEC) in infants, with collaborators Morrow, Schibler, Jiang (Cincinnati) and Ward (The Broad Institute, Cambridge, MA).
The role of human milk glycans in preventing common pulmonary infections of infants, in collaboration with Polack (Vanderbilt Medical and Buenos Aires).
Thus, the projects in the laboratory, in addition to defining the role of human milk glycans, increasingly include questions related to the ontogeny of glycans, especially those in human milk the developing gut, and their relationship to the maturing mucosal immune system. Our expertise in glycobiology is being applied toward defining the role of glycans in the gut in supporting 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.
Our research programs have been and continue to be supported primarily by the National Institutes of Health, with some support by research foundations, educational institutions, individual donations, and the private sector.