Glycan receptors specific for canine influenza infection

说明(申请人提供)：甲型流感病毒在世界各地造成大量生命损失，并继续对国内和全球公共卫生构成巨大挑战。作为人畜共患病的病原体，甲型流感病毒具有广泛的自然宿主宿主，如鸟类、猪、马和海洋哺乳动物。所有四种已知的大流行毒株都来自动物。人类通过接触野生或饲养的动物(如鸟类或猪)而感染动物源性甲型流感病毒已引起公众的严重关注。最近犬流感病毒的出现和流行扩大了这一名单，并使流感生态进一步复杂化。犬流感病毒以宠物狗为自然宿主，比以往任何时候都能最大限度地缩短动物与人类之间的距离。与与狗的接触相比，人类与这些野生或饲养的动物的接触很少。由于这些新出现的犬流感病毒在抗原性上与当代季节性流感病毒不同，表明目前人类对这些犬类流感病毒缺乏免疫力，因此犬类流感病毒对公众健康构成了潜在的重大威胁。本研究旨在探讨犬流感感染的分子机制，特别是确定决定犬流感宿主趋向性的宿主受体的特性。这项研究基于这样的假设，即犬类拥有一套独特的葡聚糖受体，决定了犬类流感宿主的取向，并且当甲型流感病毒从其他宿主跳到犬类身上时，会发生突变，与这些犬类特有的受体结合。本项目有以下两个具体目标：(1)确定确定犬流感病毒与宿主受体结合特异性的流感血凝素蛋白的病毒突变(S)；(2)鉴定犬呼吸道上皮细胞中多糖的类型和分布。这项拟议研究的成功完成将有助于阐明犬流感感染所需的流感血凝素和宿主受体的突变，从而潜在地改进抗流感药物传递策略，特别是针对糖蛋白受体的药物。本研究开发的组学和综合系统生物学方法是新颖的，可用于研究甲型流感病毒在人和其他宿主中的宿主趋向性。

DESCRIPTION (provided by applicant): Influenza A viruses are responsible for large losses of human lives around the world and continue to present a great challenge to both domestic and global public health. As a zoonotic pathogen, influenza A viruses have a wide range of natural host reservoirs, such as avian, swine, equine, and sea mammals. All four known pandemic strains are of animal origin. Human infection of animal origin influenza A viruses by contacting wild or farmed animals (e.g. birds or swine) has caused serious public concerns. Recent emergence and epidemics of canine influenza viruses have broadened this list and further complicated influenza ecology. With the pet dog as its natural host, canine influenza virus minimizes the distance between animals and humans more than ever before. Compared to contacts with dogs, human contacts with those wild or farmed animals are minimal. Because these emerging canine influenza viruses are antigenically different from contemporary seasonal influenza viruses, indicating a lack of current human herd immunity to these canine influenza viruses, canine influenza viruses present a potentially significant threat to public health. This study intends to explore the molecular mechanisms of canine influenza infection, especially to characterize the host receptors that determine canine influenza host tropisms. This study is based on the hypotheses that canines would have a unique set of glycan receptors that determine canine influenza host tropisms and that influenza A virus would mutate to bind to these canine specific receptors when jumping from other hosts to the canine. This project has the following two specific aims: (1) Identify the viral mutation(s) in influenza hemagglutinin protein that determine binding specificity between canine influenza virus and host receptor; (2) Characterize types and distribution of glycans in canine airway epithelium cells. Successful completion of the proposed studies will help elucidate both the mutations in influenza hemagglutinin and host receptors required for canine influenza infection and thus potentially improve anti-influenza drug delivery strategies, especially for those drugs targeting glycan receptors. The omics and integrative systems biology approaches developed in this study are novel and could be adapted to study the host tropisms of influenza A viruses in human and other hosts.