Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2929-E2936. doi: 10.1073/pnas.1617993114. Epub 2017 Mar 20.
Orthomyxoviruses are an important family of RNA viruses, which include the various influenza viruses. Despite global efforts to eradicate orthomyxoviral pathogens, these infections remain pervasive. One such orthomyxovirus, infectious salmon anemia virus (ISAV), spreads easily throughout farmed and wild salmonids, constituting a significant economic burden. ISAV entry requires the interplay of the virion-attached hemagglutinin-esterase and fusion glycoproteins. Preventing infections will rely on improved understanding of ISAV entry. Here, we present the crystal structures of ISAV hemagglutinin-esterase unbound and complexed with receptor. Several distinctive features observed in ISAV HE are not seen in any other viral glycoprotein. The structures reveal a unique mode of receptor binding that is dependent on the oligomeric assembly of hemagglutinin-esterase. Importantly, ISAV hemagglutinin-esterase receptor engagement does not initiate conformational rearrangements, suggesting a distinct viral entry mechanism. This work improves our understanding of ISAV pathogenesis and expands our knowledge on the overall diversity of viral glycoprotein-mediated entry mechanisms. Finally, it provides an atomic-resolution model of the primary neutralizing antigen critical for vaccine development.
正粘病毒是一类重要的 RNA 病毒，其中包括各种流感病毒。尽管全球努力根除正粘病毒病原体，但这些感染仍然普遍存在。一种正粘病毒，传染性鲑鱼贫血病毒（ISAV），很容易在养殖和野生鲑鱼中传播，给经济造成了重大负担。ISAV 的进入需要病毒附着的血凝素-酯酶和融合糖蛋白的相互作用。预防感染将依赖于对 ISAV 进入的深入了解。在这里，我们展示了未结合和与受体结合的 ISAV 血凝素-酯酶的晶体结构。在 ISAV HE 中观察到的几个独特特征在任何其他病毒糖蛋白中都没有看到。这些结构揭示了一种独特的受体结合模式，这种模式依赖于血凝素-酯酶的寡聚组装。重要的是，ISAV 血凝素-酯酶受体的结合不会引发构象重排，这表明存在一种独特的病毒进入机制。这项工作提高了我们对 ISAV 发病机制的理解，并扩展了我们对病毒糖蛋白介导的进入机制总体多样性的认识。最后，它提供了一个关键的用于疫苗开发的主要中和抗原的原子分辨率模型。
