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bioRxiv · 10.1101/2023.05.31.543096

Wolbachia-induced inhibition of O'nyong nyong virus in Anopheles mosquitoes is mediated by Toll signaling and modulated by cholesterol

Pujhari, S.·Hughes, G. L.·Pakpour, N.·Suzuki, Y.·Rasgon, J. L.
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Abstract

Enhanced host immunity and competition for metabolic resources are two main competing hypotheses for the mechanism of Wolbachia-mediated pathogen inhibition in arthropods. Using an Anopheles mosquito - somatic Wolbachia infection - Onyong nyong virus (ONNV) model, we demonstrate that the mechanism underpinning Wolbachia-mediated virus inhibition is up-regulation of the Toll innate immune pathway. However, the viral inhibitory properties of Wolbachia were abolished by cholesterol supplementation. This result was due to Wolbachia-dependent cholesterol-mediated suppression of Toll signaling rather than competition for cholesterol between Wolbachia and virus. The inhibitory effect of cholesterol was specific to Wolbachia-infected Anopheles mosquitoes and cells. These data indicate that both Wolbachia and cholesterol influence Toll immune signaling in Anopheles mosquitoes in a complex manner and provide a functional link between the host immunity and metabolic competition hypotheses for explaining Wolbachia-mediated pathogen interference in mosquitoes. In addition, these results provide a mechanistic understanding of the mode of action of Wolbachia-induced pathogen blocking in Anophelines, which is critical to evaluate the long-term efficacy of control strategies for malaria and Anopheles-transmitted arboviruses. HIGHLIGHTSO_LIWolbachia inhibits Onyong nyong virus (ONNV) in Anopheles mosquitoes. C_LIO_LIEnhanced Toll signaling is responsible for Wolbachia-induced interference of ONNV. C_LIO_LICholesterol suppresses Toll signaling to modulate Wolbachia-induced ONNV interference. C_LI

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Pujhari, S., Hughes, G. L., Pakpour, N., Suzuki, Y., Rasgon, J. L.. 2023-06-01. Wolbachia-induced inhibition of O'nyong nyong virus in Anopheles mosquitoes is mediated by Toll signaling and modulated by cholesterol. https://doi.org/10.1101/2023.05.31.543096

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