Structure of the infectious salmon anemia virus receptor complex illustrates a unique binding strategy for attachment

Abstract

<p id="d5459483e148">The infectious salmon anemia virus (ISAV), an aquatic pathogen with lethal hemorrhagic potential, decimates farmed and freshwater fish populations globally. Here, we determined the crystallographic structures of the hemagglutinin-esterase (HE) viral glycoprotein responsible for the dynamic attachment of the virus to its receptor in Atlantic salmon. We identified surface features of ISAV HE that are conserved across isolates known to cause significant economic burden to fisheries worldwide. This provides a molecular blueprint for the design of a broadly protective vaccine. Furthermore, we showed that ISAV HE has a distinct receptor recognition strategy from those of other influenza-like viruses and coronaviral HE proteins, contributing to our understanding of the diversity of viral entry mechanisms. </p><p class="first" id="d5459483e151">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. </p>