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

Abstract

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.

Drosophila melanogaster Limostatin and Its Human Ortholog Promote West Nile Virus Infection

“…Insulin priming activates the JAK/STAT antiviral pathway in D. melanogaster and mosquito cells [ 26 ]. Feeding insulin to mosquitoes suppresses the RNAi pathway and activates the JAK/STAT antiviral pathway to suppress replication of another flavivirus, Zika virus [ 67 ]. Here, we demonstrate that D. melanogaster with a mutation in the insulin suppression gene Lst is hyperinsulinemic and shows upregulated expression of genes within the antiviral JAK/STAT pathway during infection.…”

Drosophila melanogasterToll-9 elicits antiviral immunity againstDrosophilaC virus

“…For example, in Drosophila S2 cells, Sindbis virus enhances AKT phosphorylation, which supports virus replication (Patel and Hardy 2012). Insulin-mediated PI3K/AKT signaling also regulates the expression of RNAi genes Dicer2 and Argonaute2 via FoxO during West Nile and Zika virus infection (Ahlers et al 2019; Trammell et al 2022). Our study reveals that Toll-9 expression during DCV infection of S2 cells restricts AKT phosphorylation, thereby reducing viral load.…”

“…Insulin-mediated PI3K/AKT signaling also regulates the expression of RNAi genes Dicer2 and Argonaute2 via FoxO during West Nile and Zika virus infection (Ahlers et al 2019;Trammell et al 2022). Our study reveals that Toll-9 expression during DCV infection of S2 cells restricts Mammalian TLRs exhibit diverse subcellular localization, with TLRs 1, 2, 4, 5, and 6 being primarily localized on the cell membrane interacting with extracellular PAMPs, while TLRs 3, 7, 8, 9, and 10 are predominantly found in endosomes or lysosomes where they sense intracellular PAMPs such as nucleic acids (Gay et al 2014; S. M.-Y.…”

Vaccination and Control Methods of West Nile Virus Infection in Equids and Humans

“…Provisioning Culex mosquitoes with bovine insulin in their blood meal reduced WNV levels via an Aktmediated, JAK/STAT-dependent, RNAi-independent mechanism [53]. However, the simultaneous activation of JAK/STAT-and RNAi-mediated immunity in Aedes mosquitoes using small molecules reduced the prevalence and levels of Zika virus in these mosquitoes [54]. A similar approach could be used in Culex mosquitoes to combat WNV infection.…”