Wolbachia-induced inhibition of O’nyong nyong virus inAnophelesmosquitoes is mediated by Toll signaling and modulated by cholesterol

Abstract

ABSTRACTEnhanced host immunity and competition for metabolic resources are two main competing hypotheses for the mechanism ofWolbachia-mediated pathogen inhibition in arthropods. Using anAnophelesmosquito – somaticWolbachiainfection – O’nyong nyong virus (ONNV) model, we demonstrate that the mechanism underpinningWolbachia-mediated virus inhibition is up-regulation of the Toll innate immune pathway. However, the viral inhibitory properties ofWolbachiawere abolished by cholesterol supplementation. This result was due toWolbachia-dependent cholesterol-mediated suppression of Toll signaling rather than competition for cholesterol betweenWolbachiaand virus. The inhibitory effect of cholesterol was specific toWolbachia-infectedAnophelesmosquitoes and cells. These data indicate that bothWolbachiaand cholesterol influence Toll immune signaling inAnophelesmosquitoes in a complex manner and provide a functional link between the host immunity and metabolic competition hypotheses for explainingWolbachia-mediated pathogen interference in mosquitoes. In addition, these results provide a mechanistic understanding of the mode of action ofWolbachia-induced pathogen blocking in Anophelines, which is critical to evaluate the long-term efficacy of control strategies for malaria andAnopheles-transmitted arboviruses.HIGHLIGHTSWolbachiainhibits O’nyong nyong virus (ONNV) inAnophelesmosquitoes.Enhanced Toll signaling is responsible forWolbachia-induced interference of ONNV.Cholesterol suppresses Toll signaling to modulateWolbachia-induced ONNV interference.