Inhibition of betanodavirus infection by inhibitors of endosomal acidification

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Abstract
Betanodaviruses, members of the family Nodaviridae, have small positive-stranded bipartite RNA genomes and are the causal agent of viral nervous necrosis (VNN) in many species of marine farmed fish. In the aquaculture industry, outbreaks of betanodavirus infection and spread in larval and juvenile fish result in devastating damage and heavy economic loss. Although an urgent need exists to develop drugs that inhibit betanodavirus infection, there have been no reports about anti-betanodavirus drugs. Recently, it was reported that betanodaviruses were detected in the endosomes of infected cells, suggesting that betanodaviruses enter fish cells by endocytosis. This finding prompted us to examine whether blocking this endosomal pathway could provide a target for antiviral drug development. In this study, we examined the inhibitory effect of several lysosomotropic agents against betanodavirus infection in fish E-11 cells. The presence of 1 mM NH4Cl or 1 µM chloroquine in the medium inhibited the entry of betanodaviruses into cells and inhibited viral infection. The lysosomotropic agents bafilomycin A1 and monensin also inhibited virus-induced cytopathology and virus production. Our data demonstrate that inhibitors of endosomal acidification are candidates as antiviral agents against betanodavirus.