Perturbed cholesterol and vesicular trafficking associated with dengue blocking in Wolbachia-infected Aedes aegypti cells

Geoghegan, V., Stainton, K., Rainey, S. M., Ant, T. H., Dowle, A. A., Larson, T., Hester, S., Charles, P. D., Thomas, B. and Sinkins, S. P. (2017) Perturbed cholesterol and vesicular trafficking associated with dengue blocking in Wolbachia-infected Aedes aegypti cells. Nature Communications, 8, 526. (doi:10.1038/s41467-017-00610-8) (PMID:28904344) (PMCID:PMC5597582)

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Abstract

Wolbachia are 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 of Wolbachia in Aedes aegypti mosquito 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 of Wolbachia-infected Ae. aegypti cells with 2-hydroxypropyl-β-cyclodextrin restores dengue replication in Wolbachia-carrying cells, suggesting dengue is inhibited in Wolbachia-infected cells by localised cholesterol accumulation. These results demonstrate parallels between the cellular Wolbachia viral inhibition phenotype and lipid storage genetic disorders.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Geoghegan, Vincent and Sinkins, Professor Steven and Rainey, Dr Stephanie and Ant, Thomas
Authors: Geoghegan, V., Stainton, K., Rainey, S. M., Ant, T. H., Dowle, A. A., Larson, T., Hester, S., Charles, P. D., Thomas, B., and Sinkins, S. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Nature Communications 8:526
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
771541ZIKA: Vector competence and interactions with WolbachiaSteven SinkinsMedical Research Council (MRC)MC_PC_15087MVLS III - CENTRE FOR VIRUS RESEARCH