Abstract
Viral hemorrhagic septicemia virus (VHSV) is one of the most deadly infectious fish pathogens, posing a serious threat to the aquaculture industry and freshwater ecosystems worldwide. Previous work showed that VHSV sub-genotype IVb suppresses host innate immune responses, but the exact mechanism by which VHSV IVb inhibits antiviral response remains incompletely characterized. As with other novirhabdoviruses, VHSV IVb contains a unique and highly variable nonvirion (NV) gene, which is implicated in viral replication, virus-induced apoptosis and regulating interferon (IFN) production. However, the molecular mechanisms underlying the role of IVb NV gene in regulating viral or cellular processes is poorly understood. Compared to the wild-type recombinant (rWT) VHSV, mutant VHSV lacking a functional IVb NV reduced IFN expression and compromised innate immune response of the host cells by inhibiting translation. VHSV IVb infection increased phosphorylated eukaryotic initiation factor 2α (p-eIF2α), resulting in host translation shutoff. However, VHSV IVb protein synthesis proceeds despite increasing phosphorylation of eIF2α. During VHSV IVb infection, eIF2α phosphorylation was mediated via PKR-like endoplasmic reticulum kinase (PERK) and was required for efficient viral protein synthesis, but shutoff of host translation and IFN signaling was independent of p-eIF2α. Similarly, IVb NV null VHSV infection induced less p-eIF2α, but exhibited decreased viral protein synthesis despite increased levels of viral mRNA. These findings show a role for IVb NV in VHSV pathogenesis by utilizing the PERK-eIF2α pathway for viral-mediated host shutoff and interferon signaling to regulate host cell response.
Highlights
Viral hemorrhagic septicemia virus (VHSV), known as Piscine novirhabdovirus, is one of the world’s most deadly infectious fish pathogens, with a mortality rate as high as 100% in juvenile fish.VHSV infects more than 90 marine and freshwater species worldwide, posing a serious threat to the aquaculture industry
To better examine the role of VHSV IVb NV on IFN signaling, we compared the effect of WT IVb NV to NV-ATG, in which the two ATG start codons of the IVb NV open reading frame were mutated to TGA codons (NV-ATG)
These results suggest that removal of IVb NV may inhibit the ability of VHSV to overcome the inhibition of host translation and synthesize its own viral proteins
Summary
Viral hemorrhagic septicemia virus (VHSV), known as Piscine novirhabdovirus, is one of the world’s most deadly infectious fish pathogens, with a mortality rate as high as 100% in juvenile fish. VHSV infects more than 90 marine and freshwater species worldwide, posing a serious threat to the aquaculture industry. VHSV has been classified into four individual genotypes (I-IV) based on geographic location and genomic sequence similarities of G and N genes [5,6]. In 2005, VHSV IVb strain was detected in the Great Lakes as a major cause of mortality in the naïve fish population, posing a threat to farmed fish. VHSV IVb provides a new model to study invasive virus species and the mechanism of virulence of viruses that pose threat to the aquaculture industry [7,8,9,10]
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