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

布鲁杆菌病会导致牛的自然流产和与受感染动物接触的人的严重衰弱不适。在加拿大，野生动物种群（野牛、麋鹿、驯鹿）中存在布鲁氏杆菌，疾病可从这些种群传播给家养牛群或人类。由于对养牛业的经济影响和人类的疾病潜力，美国已经花费了35亿美元试图为其牛群接种疫苗，并在追踪牛群中的潜在病例方面保持警惕。目前的动物疫苗是布鲁氏菌的减毒株，但这造成了不切实际的情况。动物和人类布鲁氏菌病的推定诊断取决于布鲁氏菌细胞表面多糖抗原抗体的检测，但由于接种疫苗的动物表现出与布鲁氏菌强毒株感染的牛相似的抗体应答，因此存在混淆。 多糖包被细菌，其抗体保护细菌免受感染，并且如针对布鲁氏菌所述，抗体检测用于感染的诊断。我们的合成碳水化合物研究使我们能够了解细菌抗原识别的分子基础，广泛的抗体。我们将利用这一基础来指导布鲁氏菌A和M多糖抗原的活性亚片段的设计和合成，目的是创造对兽医学重要的精确诊断抗原。 这项研究的第二个目标是发现更简单，更有效的方法来将抗原传递给树突细胞，树突细胞处理外来抗原并确保有效的免疫反应。树突状细胞上的C型凝集素是结合碳水化合物的蛋白质。我们将合成寡糖并以多个拷贝展示它们，以便它们与C型凝集素Dectin-1充分紧密地结合，以刺激该途径的效应物，从而导致抗原摄取和强大的免疫应答。 建议的基础化学发现研究是必要的，并支持我们的努力，以了解细胞控制的免疫反应，碳水化合物抗原。

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.