All living cells in nature display a dense and complex array of sugar chains (glycans) in their cell surface and extracellular compartments. Vertebrate glycans often terminate their outer ends with members of a family of sugars called Sialic Acids (Sias). These Sias are attached to underlying glycans in various linkages, and are modified in multiple ways. Such diversity in Sia linkages and modifications are expressed in specific patterns, which change markedly during normal and abnormal processes. The long-term goal of this grant has been to unravel mechanisms generating this Sia diversity, and to elucidate its significance in health and disease. During the last funding period we directed all attention to the human-specific genetic loss of the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc). Given our current exciting and novel findings, we will continue this focus. Thus, the entire proposal is focused on interesting implications of the single oxygen atom that differs between Neu5Gc and its precursor Neu5Ac, some of which we have elucidated. In the current proposal we focus on our surprising discovery that human cells can take up and metabolically incorporate exogenous Neu5Gc, and the relevance of this finding to human dietary intake of Neu5Gc, which is enriched in red meats. The resulting presence of foreign Neu5Gc on the surface of some human cell types in the body is the first known example of such a process. While the extent of incorporation is small, it is relevant because all humans have a variable and complex circulating antibody response to Neu5Gc. Our initial evidence shows that this unusual combination of antigen and antibody in the same individual generates a novel form of chronic inflammation, the first example of such a process. Thus Neu5Gc loss in humans has implications ranging from biochemical, cell biological and gastrointestinal issues involving Neu5Gc uptake, incorporation and metabolism in cells and tissues, to the origins, diversity and significance of anti-Neu5Gc antibodies in humans, to the need to eliminate Neu5Gc from human tissues. Further interest arises from our unexpected finding that the N-glycolyl group derived from Neu5Gc metabolism can enter other metabolic pathways, generating previously unknown glycan structures and potential new targets for autoantibodies. Besides biochemical, cell biological and epidemiological studies of human cells and human samples, we will also use mice with a human-like defect in Neu5Gc production. We propose to complete elucidation of the metabolism of N-glycolyl groups in human and animal cells, and in such mice. We will also explore mechanisms generating the diverse and variable range of anti-Neu5Gc antibodies, including attempts to clone monoclonal human antibodies. In parallel, we will study selected consequences of interactions between anti- Neu5Gc antibodies and Neu5Gc-containing glycans in mice and humans, asking if the resulting inflammation can help explain increased risks of heart disease, cancer and diabetes associated with red meat consumption. In the long run it may become necessary to develop non-toxic ways to eliminate Neu5Gc from the body.

Public Health Relevance

Humans differ from other mammals in that our bodies are deficient in producing a type of cell surface molecule called Neu5Gc. We have made a surprising discovery that the human body incorporates Neu5Gc from dietary intake of red meats, and that antibodies against this foreign molecule generate inflammation, which may help explain the increased risk of heart disease, cancer and diabetes associated with red meat consumption. We propose a range of novel studies ranging from basic biochemical, cell biological and physiological issues, to the origins, diversity and significance of anti-Neu5Gc antibodies, to the ultimate need to eliminate Neu5Gc from the human body.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM032373-34
Application #
9391678
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Somers, Scott D
Project Start
1983-08-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
34
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Siddiqui, Shoib; Schwarz, Flavio; Springer, Stevan et al. (2017) Studies on the Detection, Expression, Glycosylation, Dimerization, and Ligand Binding Properties of Mouse Siglec-E. J Biol Chem 292:1029-1037
Naito-Matsui, Yuko; Davies, Leela R L; Takematsu, Hiromu et al. (2017) Physiological Exploration of the Long Term Evolutionary Selection against Expression of N-Glycolylneuraminic Acid in the Brain. J Biol Chem 292:2557-2570
Owen, C David; Tailford, Louise E; Monaco, Serena et al. (2017) Unravelling the specificity and mechanism of sialic acid recognition by the gut symbiont Ruminococcus gnavus. Nat Commun 8:2196
Gao, Xiang; Deng, Lingquan; Stack, Gabrielle et al. (2017) Evolution of host adaptation in the Salmonella typhoid toxin. Nat Microbiol 2:1592-1599
Khedri, Zahra; Xiao, An; Yu, Hai et al. (2017) A Chemical Biology Solution to Problems with Studying Biologically Important but Unstable 9-O-Acetyl Sialic Acids. ACS Chem Biol 12:214-224
Okerblom, Jonathan J; Schwarz, Flavio; Olson, Josh et al. (2017) Loss of CMAH during Human Evolution Primed the Monocyte-Macrophage Lineage toward a More Inflammatory and Phagocytic State. J Immunol 198:2366-2373
Varki, Ajit (2017) Biological roles of glycans. Glycobiology 27:3-49
Okerblom, Jonathan; Varki, Ajit (2017) Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N-Glycolylneuraminic Acid. Chembiochem 18:1155-1171
Siddiqui, Shoib S; Springer, Stevan A; Verhagen, Andrea et al. (2017) The Alzheimer's disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool. J Biol Chem 292:15312-15320
Bergfeld, Anne K; Lawrence, Roger; Diaz, Sandra L et al. (2017) N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils. Proc Natl Acad Sci U S A 114:E8155-E8164

Showing the most recent 10 out of 134 publications