Alterations in the Aedes aegypti Transcriptome during Infection with West Nile, Dengue and Yellow Fever Viruses

Tonya M Colpitts,Stephen Higgs,Fabiana M Feitosa,Erol Fikrig,Gong Cheng,Sebastian Kurscheid,Manoj N Krishnan,Penghua Wang,Dana L Vanlandingham,Jonathan Cox

doi:10.1371/journal.ppat.1002189

Abstract

West Nile (WNV), dengue (DENV) and yellow fever (YFV) viruses are (re)emerging, mosquito-borne flaviviruses that cause human disease and mortality worldwide. Alterations in mosquito gene expression common and unique to individual flaviviral infections are poorly understood. Here, we present a microarray analysis of the Aedes aegypti transcriptome over time during infection with DENV, WNV or YFV. We identified 203 mosquito genes that were ≥5-fold differentially up-regulated (DUR) and 202 genes that were ≥10-fold differentially down-regulated (DDR) during infection with one of the three flaviviruses. Comparative analysis revealed that the expression profile of 20 DUR genes and 15 DDR genes was quite similar between the three flaviviruses on D1 of infection, indicating a potentially conserved transcriptomic signature of flaviviral infection. Bioinformatics analysis revealed changes in expression of genes from diverse cellular processes, including ion binding, transport, metabolic processes and peptidase activity. We also demonstrate that virally-regulated gene expression is tissue-specific. The overexpression of several virally down-regulated genes decreased WNV infection in mosquito cells and Aedes aegypti mosquitoes. Among these, a pupal cuticle protein was shown to bind WNV envelope protein, leading to inhibition of infection in vitro and the prevention of lethal WNV encephalitis in mice. This work provides an extensive list of targets for controlling flaviviral infection in mosquitoes that may also be used to develop broad preventative and therapeutic measures for multiple flaviviruses.

Highlights

West Nile (WNV), dengue (DENV) and yellow fever (YFV) viruses are globally important, re-emerging mosquito-borne flaviviruses that cause widespread human disease and mortality [1]
Dengue (DENV), West Nile (WNV) and Yellow Fever (YFV) viruses are responsible for severe human disease and mortality worldwide
We investigate the alterations in gene expression across the entire Aedes aegypti genome during infection with DENV, YFV and WNV over time

Summary

Introduction

West Nile (WNV), dengue (DENV) and yellow fever (YFV) viruses are globally important, re-emerging mosquito-borne flaviviruses that cause widespread human disease and mortality [1]. There are an estimated 100 million cases per year, with over 500,000 cases of potentially fatal dengue hemorrhagic fever [3,4]. There is no specific treatment for either West Nile or dengue virus, and efforts to create an effective dengue vaccine have been hindered due to safety concerns and potential antibody-dependent enhancement [3,5]. YFV is endemic to tropical regions of Africa and South America and causes a febrile illness often involving hemorrhagic manifestations with fatality rates up to 50% [6,7]. There is a YFV vaccine available but it is underutilized in many countries with endemic YFV and no specific antiviral is available [8]

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