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，可导致严重贫血。这种疾病在受感染的农场内进展缓慢，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、美国和世界其他国家引起了重大疾病暴发。2012年7月，在纽芬兰确诊的疫情导致45万条养殖鲑鱼被销毁。该病毒造成了重大经济损失，并对鲑鱼养殖的生存能力构成重大威胁。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鲑鱼宿主的基本生物学原理。****ISAV是正黏液病毒家族中的一种负链、节段性ssRNA病毒，类似于人流感病毒a。病毒显示两种参与其进入的表面糖蛋白：(a) 42 kDa的血凝素酯酶（HE），负责受体结合、向性和受体破坏/释放；(b)具有融合活性的50 kDa F糖蛋白。这两种蛋白对ISAV的生命周期和发病机制至关重要。ISAV是唯一已知的在不同蛋白上具有附着和融合活性的正黏液病毒家族成员，了解这一过程为提供新的模型原理提供了独特的机会。使用可靠的结合，以及创新的生物物理方法，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，以及(2)ISAV f介导的融合。病毒糖蛋白的结构和功能研究需要付出巨大的努力，因为结果将对我们在原子水平上理解ISAV的附着、进入和发病机制至关重要。此外，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. **********