Characterization of a glycoprotein entry complex from a novel orthomyxovirus

新型正粘病毒糖蛋白进入复合物的表征

• 批准号: 435607-2013
• 负责人: Lee, Jeffrey
• 金额: $ 4.59万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=657028
• 关键词: Characterization; glycoprotein; entry; complex; novel

Infectious salmon anaemia virus (ISAV) is a significant emerging disease of Atlantic farmed salmon that causes severe anemia. The disease can progress slowly throughout an infected farm, and mortality rates may approach 100%. The virus was first identified in Norway in 1984, but over the last 25 years ISAV has caused major disease outbreaks in Canada, U.S., and other countries around the world. In July 2012, a confirmed outbreak in Newfoundland prompted the destruction of 450,000 farmed salmon. The virus has caused major economic losses and is a major threat to the viability of salmon farming. Currently, very little is known about its viral lifecycle. Additional studies are urgently needed to understand the basic biology of how this virus enters its salmon host.****ISAV is a negative-strand, segmented ssRNA virus in the orthomyxovirus family, similar to human influenza virus A. The virus displays two surface glycoproteins that are involved in its entry: (a) a 42 kDa hemagglutinin-esterase (HE) that is responsible for receptor engagement, tropism and receptor destruction/release; and (b) a 50 kDa F glycoprotein with fusion activity. These two proteins are critical to the ISAV lifecycle and pathogenesis. ISAV is the only known member of the orthomyxovirus family with attachment and fusion activities on different proteins, and understanding this process offers a unique opportunity to contribute new model principles. Using a combination of tried-and-true, as well as innovative biophysical approaches, we aim to determine the molecular determinants of: (1) ISAV HE-mediated receptor binding and release, and (2) ISAV F-mediated fusion. Structural and functional studies of viral glycoproteins warrant a significant effort as the results will be critical to our atomic-level understanding of ISAV attachment, entry and pathogenesis. Moreover, any structural models obtained will deliver a molecular blueprint for the development of novel preventative strategies. **********

传染性鲑鱼贫血病毒（ISAV）是一种引起大西洋养殖鲑鱼严重贫血的重要新兴疾病。这种疾病可以在整个受感染的农场缓慢进展，死亡率可能接近100%。该病毒于1984年首次在挪威被发现，但在过去的25年里，ISAV在加拿大，美国，和世界上其他国家。2012年7月，纽芬兰确认爆发疫情，导致45万条养殖鲑鱼被销毁。该病毒已造成重大经济损失，并对鲑鱼养殖的可行性构成重大威胁。目前，对其病毒生命周期知之甚少。迫切需要进一步的研究来了解这种病毒如何进入其鲑鱼宿主的基本生物学。ISAV是正粘病毒科中的一种负链、分段ssRNA病毒，与人流感病毒A相似。该病毒显示出参与其进入的两种表面糖蛋白：（a）42 kDa血凝素酯酶（HE），其负责受体接合、向性和受体破坏/释放;和（B）具有融合活性的50 kDa F糖蛋白。这两种蛋白质对ISAV的生命周期和发病机制至关重要。ISAV是正粘病毒家族中唯一已知的在不同蛋白质上具有附着和融合活性的成员，了解这一过程为贡献新的模型原理提供了独特的机会。使用经过验证的和真实的，以及创新的生物物理方法的组合，我们的目标是确定分子决定因素：（1）ISAV HE介导的受体结合和释放，和（2）ISAV F介导的融合。病毒糖蛋白的结构和功能的研究保证了显着的努力，因为结果将是至关重要的，我们的原子水平的理解ISAV的附着，进入和发病机制。此外，获得的任何结构模型将为开发新的预防策略提供分子蓝图。 **********