Exploring common modulations induced by three fish RNA viruses in turbot (Scophthalmus maximus): Cholesterol, vitamin D3 and retinol metabolism as shared targets

Abstract

Viral diseases pose a significant challenge in the fish aquaculture sector, as effective vaccines are lacking for many of them, and there are no approved antiviral treatments for use in aquaculture. Understanding how fish respond to diseases is fundamental for developing antiviral strategies, with a strong preference for broad-spectrum and economically accessible options. Therefore, identifying specific processes affected by multiple pathogens could help identify targets for wide-range therapeutic intervention. In this work, we conducted RNA-Seq to analyze the response to three RNA viruses (VHSV, IPNV, and RGNNV) at 3 days postinfection in flatfish turbot. For this purpose, head kidney samples from turbot infected with the different viruses and brain samples from the animals infected with RGNNV, as along with their corresponding uninfected controls, were sequenced. In head kidney samples, we found that the three RNA viruses shared the modulation of a set of genes that were predominantly involved in three metabolic pathways: cholesterol biosynthesis, vitamin D3 metabolism and retinol (vitamin A) metabolism. This observation, together with the systemic modulation of cholesterol and retinoic acid levels following viral infection, suggests that these metabolic processes could play a significant role in the antiviral immune response and/or the pathogenesis of these fish RNA viruses. Based on this, we used different metabolic modulators and metabolites to bring some light to the significance of these disturbances in the context of the viral infections. Statins (inhibitors of cholesterol synthesis) demonstrated in vitro antiviral activity, while valspodar (an inhibitor of cholesterol efflux) exhibited a proviral effect. Similarly, calcitriol (the active form of vitamin D3), retinol, and retinoic acid exhibited potent antiviral activity against the three RNA viruses. These findings underscore that metabolism represents a compelling target for broad-spectrum antiviral interventions, and future studies on immunometabolism will provide valuable insights for identifying specific therapeutic targets to fight fish viral diseases.