Deciphering host responses to insulin signaling and West Nile virus infection in insects.

Mosquitoes are the primary vectors of West Nile virus (WNV), and infection with the virus can lead to neuroinvasive disease, posing a serious threat to human health. Despite the increasing exposure to WNV and the expanding range of the vector mosquito, there are limited therapies available to prevent or treat the infection. A previous study from our lab using a pathway-unbiased screening approach in adult Drosophila melanogaster identified that a mutation in the insulin receptor gene rendered fruit flies more susceptible to WNV infection. We further demonstrated that treatment with mammalian insulin to activate insulin/insulin-like growth factor signaling (IIS) reduced WNV infection in both fruit flies and adult female Culex quinquefasciatus via an Akt-ERK-JAK/STAT signaling axis that was not dependent on anti-viral RNA interference activity. In addition to targeted approaches for uncovering mechanisms of IIS-mediated anti-viral activity in flies and mosquitoes, we also employ functional genomics methods to survey genome-wide host responses to IIS. These approaches revealed that mechanisms of G protein-coupled receptor signaling and cell proliferation were central to an IIS-mediated host response to WNV in fruit flies. Moreover, in mosquitoes, mechanisms of hydrolysis, oxidation, and proteolysis controlled IIS-mediated immunity to WNV. Finally, orthology mapping between Drosophila and Culex genesets uncovered a number of genes that were similarly regulated during IIS and WNV infection in both flies and mosquitoes. Taken together, these results elucidate new host responses to insulin signaling and virus infection in insects that may help combat the spread of WNV in mosquitoes and disease in humans.