Insulin Potentiates JAK/STAT Signaling to Broadly Inhibit Flavivirus Replication in Insect Vectors

The World Health Organization estimates that more than half of the world’s population is at risk for vector-borne diseases, including arboviruses. Because many arboviruses are mosquito borne, investigation of the insect immune response will help identify targets to reduce the spread of arboviruses. Here, we use a genetic screening approach to identify an insulin-like receptor as a component of the immune response to arboviral infection. We determine that vertebrate insulin reduces West Nile virus (WNV) replication in Drosophila melanogaster as well as WNV, Zika, and dengue virus titers in mosquito cells. Mechanistically, we show that insulin signaling activates the JAK/STAT, but not RNAi, pathway via ERK to control infection in Drosophila cells and Culex mosquitoes through an integrated immune response. Finally, we validate that insulin priming of adult female Culex mosquitoes through a blood meal reduces WNV infection, demonstrating an essential role for insulin signaling in insect antiviral responses to human pathogens. [Display omitted] •Identified insulin-like receptor as anti-flaviviral in a screen of adult Drosophila•Insulin signaling inhibits antiviral RNAi while activating the JAK/STAT pathway•Flavivirus replication is reduced in mosquito cells primed with mammalian insulin•West Nile virus titer is reduced in Culex mosquitoes that are fed mammalian insulin The world’s population is at risk for infection with several flaviviruses. Ahlers et al. use a living library of insects to determine that an insulin-like receptor controls West Nile virus infection. Insulin signaling is antiviral via the JAK/STAT pathway in both fly and mosquito models and against a range of flaviviruses.