Coupled small molecules target RNA interference and JAK/STAT signaling to reduce Zika virus infection in Aedes aegypti

Author summaryArboviruses pose a significant threat to humans and are an increasing concern as a result of climate change and expanding vector-competent populations. The recent Zika outbreaks demonstrate that mosquito-borne illnesses caused by viral infection remain a prominent and evolving threat that must be actively addressed. As there are currently no post-exposure therapeutics available for Zika virus infection, reducing transmission and, in turn, the likelihood of infection would provide sizeable benefit for human populations most at risk. Here, we show that readily available small molecules can be repurposed to effectively reduce viral replication and likelihood of transmission for a clinically relevant strain of Zika in vector competent mosquitoes. Furthermore, we show how two insulin-mediated canonical antiviral pathways are simultaneously activated in our drug treatment regimen to reduce virus levels in mosquito saliva, through which virus is transmitted to humans. Together, we demonstrate the viability of targeting insulin signaling as a means of reducing the rate of mosquito infection and decreased transmission of Zika virus. The recent global Zika epidemics have revealed the significant threat that mosquito-borne viruses pose. There are currently no effective vaccines or prophylactics to prevent Zika virus (ZIKV) infection. Limiting exposure to infected mosquitoes is the best way to reduce disease incidence. Recent studies have focused on targeting mosquito reproduction and immune responses to reduce transmission. Previous work has evaluated the effect of insulin signaling on antiviral JAK/STAT and RNAi in vector mosquitoes. Specifically, insulin-fed mosquitoes resulted in reduced virus replication in an RNAi-independent, ERK-mediated JAK/STAT-dependent mechanism. In this work, we demonstrate that targeting insulin signaling through the repurposing of small molecule drugs results in the activation of both RNAi and JAK/STAT antiviral pathways. ZIKV-infected Aedes aegypti were fed blood containing demethylasterriquinone B1 (DMAQ-B1), a potent insulin mimetic, in combination with AKT inhibitor VIII. Activation of this coordinated response additively reduced ZIKV levels in Aedes aegypti. This effect included a quantitatively greater reduction in salivary gland ZIKV levels up to 11 d post-bloodmeal ingestion, relative to single pathway activation. Together, our study indicates the potential for field delivery of these small molecules to substantially reduce virus transmission from mosquito to human. As infections like Zika virus are becoming more burdensome and prevalent, understanding how to control this family of viruses in the insect vector is an important issue in public health.

Automated summary

This study demonstrates that targeting insulin signaling through the repurposing of small molecule drugs can effectively reduce viral replication and transmission of Zika virus. Activation of RNAi and JAK/STAT antiviral pathways by insulin signaling leads to a significant reduction in virus levels in mosquitoes. The findings suggest a potential field delivery approach to reduce virus transmission from mosquitoes to humans.