Molecular Recognition of Complex Glycans by Antibodies and Dendritic Cell C-type Lectins

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Brucellosis causes spontaneous abortion in cattle and a serious debilitating malaise in humans who come in contact with infected animals. In Canada there are repositories of Brucella in wild animal populations (bison, elk, caribou) from which the disease can be spread to domestic cattle herds or humans. Because of the economic effect on the cattle business and the disease potential in humans, the US has spent $3.5 billion trying to vaccinate its cattle herds and is vigilant in tracking potential cases within herds. The current animal vaccine is an attenuated strain of Brucella but this creates an impractical situation. Presumptive diagnosis of brucellosis in animals and humans depends on detection of antibodies to Brucella cell surface polysaccharide antigens but is confounded because vaccinated animals manifest an antibody response similar to that observed in cattle infected by a virulent strain of Brucella. Polysaccharides coat bacteria and antibodies to them protect against infection, and as mentioned for Brucella, detection of antibodies is used for diagnosis of infection. Our synthetic carbohydrate research has enabled us to understand the molecular basis for bacterial antigen recognition by a wide range of antibodies. We will use this foundation to guide the design and synthesis of active sub-fragments of Brucella A and M polysaccharide antigens, with the objective of creating precise diagnostic antigens important to veterinary medicine. A second objective of this research is to discover simpler and more effective ways to deliver antigens to dendritic cells, the cells that process foreign antigens and ensure an effective immune response. C-type lectins on dendritic cells are proteins that bind carbohydrates. We will synthesize oligosaccharides and display them in multiple copies so that they bind the C-type lectin, Dectin-1 sufficiently tightly to stimulate effectors of this pathway leading to antigen uptake and a robust immune response. The proposed fundamental chemistry discovery research is necessary and underpins our efforts to understand cellular control of the immune response to carbohydrate antigens.