Reduced insulin/IGF-1 signalling upregulates two anti-viral immune pathways, decreases viral load and increases survival under viral infection in C. elegans

Reduced insulin/IGF-1 signalling (rIIS) improves survival across diverse taxa and there is a growing interest in its role in regulating immune function. Whilst rIIS can improve anti-bacterial resistance, the consequences for anti-viral immunity are yet to be systematically examined. Here, we show that rIIS in adult Caenorhabditis elegans increases the expression of key genes in two different anti-viral immunity pathways, whilst reducing viral load in old age, increasing survival and reducing rate-of-senescence under infection by naturally occurring positive-sense single-stranded RNA Orsay virus. We found that both drh-1 in the anti-viral RNA interference (RNAi) pathway and cde-1 in the terminal uridylation-based degradation of viral RNA pathway were upregulated in early adulthood under rIIS and increased anti-viral resistance was not associated with reproductive costs. Remarkably, rIIS increased anti-viral gene expression only in infected worms, potentially to curb the costs of constitutively upregulated immunity. RNA viruses are found across taxa from plants to mammals and we demonstrate a novel role for rIIS in regulating resistance to viral infection. We therefore highlight this evolutionarily conserved signalling pathway as a promising therapeutic target to improve anti-viral immunity.