Highlights d Identified insulin-like receptor as anti-flaviviral in a screen of adult Drosophila d Insulin signaling inhibits antiviral RNAi while activating the JAK/STAT pathway d Flavivirus replication is reduced in mosquito cells primed with mammalian insulin d West Nile virus titer is reduced in Culex mosquitoes that are fed mammalian insulin

SUMMARYThe World Health Organization estimates that over half of the world’s population is at risk for vector-borne diseases, such as those caused by arboviral infection. Because many arboviruses are mosquito-borne, investigation of the insect immune response will help identify targets that could reduce the spread of these viruses by the mosquito. In this study, we used a genetic screening approach to identify insulin-like receptor as a novel component of the immune response to arboviral infection. We determined 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 showed that insulin signaling activates the JAK/STAT, but not RNAi, pathway to control infection. Finally, we validated 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 emerging human pathogens.