Immunogenetics of antiviral immunity in ducks

鸭抗病毒免疫的免疫遗传学

• 批准号: RGPIN-2020-04668
• 负责人: Magor, Katharine
• 金额: $ 3.64万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740109
• 关键词: Immunogenetics; antiviral; immunity; ducks

My NSERC research program is focused on the immunogenetics of the wild duck population and its influence on their role as host of influenza. We know that 15-30% of wild ducks are infected with influenza in Canadian lakes at any time. We would like to know how ducks clear the virus, and be able to correlate the genetics of ducks with their disease susceptibility/resistance. We think ducks with one unique type of gene are better at flu defense, and we will test that hypothesis by sampling blood and flu infection status of wild ducks in Alberta. Alberta is the convergence of several North American flyways, so is ideal for flu surveillance. This would be useful to know for duck farming, as well as conservation efforts aimed at maintaining a healthy population of wild ducks in the ecosystem. Three arms of the immune response are involved in clearing viruses; antibodies, adaptive immunity involving white blood cells that kill infected cells, and innate immunity. We believe that impaired adaptive immunity is responsible for the duck's exploitation as the host of most strains of influenza, while robust innate immunity allows them to survive highly pathogenic avian influenza. Our long-term goal is to understand these host-pathogen interactions from an immunology perspective, and understand the role of genetic diversity in host immune responses. Research goals focus on investigating gene order, diversity and expression in the MHC region of the genome. The genes that control the host immune response are located on one chromosome in the Major Histocompatibility Complex. The diversity of these genes in the species determines their success against viral pathogens. We are exploring the diversity of genes that control three kinds of white blood cells, the helper and cytotoxic T cells and the B cells that make antibodies. Different MHC genotypes have different immune responses to virus and to vaccines. We are also exploring other MHC-linked genes, called TRIM genes, which upregulate innate immune responses. Stronger innate responses are instructive for overall better immune responses. Antibody repertoire analyses of wild ducks may provide insight into generation of broadly neutralizing anti-influenza antibodies (the holy grail for influenza vaccines) and from experimental infections, therapeutics to combat highly pathogenic avian influenza. Here we examine the diversity and function of genes involved in controlling the duck immune response; 1) MHC class I that presents viral peptides to cytotoxic T cells, 2) MHC class II that presents particles taken up by macrophages and presented to helper T cells. Helper T cells turn on cytotoxic T cells and B cells that make antibodies; and 3) the MHC-linked TRIM27-L protein that turns up the innate immune response. Understanding the diversity of genes involved in defense against influenza in the reservoir host may help us understand selective forces driving evolution of influenza strains circulating in the environment.

我的NSERC研究项目的重点是野鸭种群的免疫遗传学及其对它们作为流感宿主的作用的影响。我们知道，在加拿大的湖泊中，任何时候都有15-30%的野鸭感染了流感。我们想知道鸭子是如何清除病毒的，并能够将鸭子的遗传与它们的疾病易感性/抗性联系起来。我们认为，拥有一种独特基因的鸭子更善于防御流感，我们将通过对阿尔伯塔省野鸭的血液和流感感染状况取样来验证这一假设。艾伯塔省是北美几条航线的交汇处，因此是流感监测的理想地点。了解这一点对养鸭以及旨在维持生态系统中野鸭健康种群的保护工作都很有用。清除病毒涉及免疫反应的三个方面；抗体、适应性免疫（包括杀死被感染细胞的白细胞）和先天免疫。我们认为，适应性免疫受损是鸭子成为大多数流感病毒宿主的原因，而强大的先天免疫使它们能够在高致病性禽流感中存活下来。我们的长期目标是从免疫学角度了解这些宿主-病原体相互作用，并了解遗传多样性在宿主免疫反应中的作用。研究目标集中在研究基因组MHC区域的基因顺序、多样性和表达。控制宿主免疫反应的基因位于主要组织相容性复合体的一条染色体上。物种中这些基因的多样性决定了它们能否成功对抗病毒病原体。我们正在探索控制三种白细胞的基因的多样性，辅助T细胞和细胞毒性T细胞以及产生抗体的B细胞。不同的MHC基因型对病毒和疫苗有不同的免疫反应。我们也在探索其他与mhc相关的基因，称为TRIM基因，它可以上调先天免疫反应。更强的先天反应对整体更好的免疫反应具有指导意义。对野鸭的抗体库分析可能有助于了解广泛中和的抗流感抗体（流感疫苗的圣杯）的产生，以及从实验性感染中获得对抗高致病性禽流感的治疗方法。在这里，我们研究了参与控制鸭子免疫反应的基因的多样性和功能；1) MHC I类向细胞毒性T细胞呈递病毒肽，2)MHC II类呈递被巨噬细胞吸收并呈递辅助T细胞的颗粒。辅助性T细胞启动产生抗体的细胞毒性T细胞和B细胞；3)与mhc相关的TRIM27-L蛋白，该蛋白会引发先天免疫反应。了解宿主中参与流感防御的基因多样性可能有助于我们理解驱动环境中循环的流感毒株进化的选择性力量。