Perturbed cholesterol and vesicular trafficking associated with dengue blocking in Wolbachia-infected Aedes aegypti cells
Geoghegan V., Stainton K., Rainey SM., Ant TH., Dowle AA., Larson T., Hester S., Charles PD., Thomas B., Sinkins SP.
AbstractWolbachiaare intracellular maternally inherited bacteria that can spread through insect populations and block virus transmission by mosquitoes, providing an important approach to dengue control. To better understand the mechanisms of virus inhibition, we here perform proteomic quantification of the effects ofWolbachiainAedes aegyptimosquito cells and midgut. Perturbations are observed in vesicular trafficking, lipid metabolism and in the endoplasmic reticulum that could impact viral entry and replication.Wolbachia-infected cells display a differential cholesterol profile, including elevated levels of esterified cholesterol, that is consistent with perturbed intracellular cholesterol trafficking. Cyclodextrins have been shown to reverse lipid accumulation defects in cells with disrupted cholesterol homeostasis. Treatment ofWolbachia-infectedAe.aegypticells with 2-hydroxypropyl-β-cyclodextrin restores dengue replication inWolbachia-carrying cells, suggesting dengue is inhibited inWolbachia-infected cells by localised cholesterol accumulation. These results demonstrate parallels between the cellularWolbachiaviral inhibition phenotype and lipid storage genetic disorders.