Expanding the canon: Non-classical mosquito genes at the interface of arboviral infection

Mosquito transmitted viruses cause significant morbidity and mortality in human populations. Despite the use of insecticides and other measures of vector control, arboviral diseases are on the rise. One potential solution for limiting disease transmission to humans is to render mosquitoes refractory to viral infection through genetic modification. Substantial research effort in Drosophila, Aedes and Anopheles has helped to define the major innate immune pathways, including Toll, IMD, Jak/Stat and RNAi, however we still have an incomplete picture of the mosquito antiviral response. Transcriptional profiles of virus-infected insects reveal a much wider range of pathways activated by the process of infection. Within these lists of genes are unexplored mosquito candidates of viral defense. Wolbachia species are endosymbiotic bacteria that naturally limit arboviral infection in mosquitoes. Our understanding of the Wolbachia-mediated viral blocking mechanism is poor, but it does not appear to operate via the classical immune pathways. Herein, we reviewed the transcriptomic response of mosquitoes to multiple viral species and put forth consensus gene types/families outside the immune canon whose expression responds to infection, including cytoskeleton and cellular trafficking, the heat shock response, cytochromes P450, cell proliferation, chitin and small RNAs. We then examine emerging evidence for their functional role in viral resistance in diverse insect and mammalian hosts and their potential role in Wolbachia-mediated viral blocking. These candidate gene families offer novel avenues for research into the nature of insect viral defense.