Characterization of a glycoprotein entry complex from a novel orthomyxovirus

传染性鲑鱼贫血病毒(ISAV)是大西洋养殖鲑鱼的一种重要新发疾病，可引起严重贫血。这种疾病可能在受感染的农场缓慢发展，死亡率可能接近100%。该病毒于1984年在挪威首次发现，但在过去的25年里，ISAV在加拿大、美国和世界其他国家引发了重大疾病暴发。2012年7月，纽芬兰确认爆发疫情，导致45万条养殖三文鱼被销毁。该病毒已造成重大经济损失，并对鲑鱼养殖业的生存能力构成重大威胁。目前，人们对其病毒生命周期知之甚少。ISAV是正粘病毒家族中的一种负链、节段性的单链RNA病毒，与人类流感病毒A相似。该病毒表现出两种与其进入宿主有关的表面糖蛋白：(A)42 kDa血凝素-酯酶(HE)，负责受体结合、趋向性和受体破坏/释放；(B)50 kDa F糖蛋白，具有融合活性。这两种蛋白在ISAV的生命周期和致病过程中起着关键作用。ISAV是正粘病毒家族中唯一已知的对不同蛋白质具有附着和融合活性的成员，了解这一过程提供了一个独特的机会来贡献新的模型原理。我们的目标是综合运用行之有效的生物物理方法和创新的生物物理方法来确定：(1)ISAV HE介导的受体结合和释放，以及(2)ISAV F介导的融合的分子决定因素。对病毒糖蛋白的结构和功能的研究需要付出大量的努力，因为这些结果将对我们在原子水平上理解ISAV的附着、进入和致病机制至关重要。此外，所获得的任何结构模型都将为开发新的预防策略提供分子蓝图。**********

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. **********