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

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.

An Antiviral Role for Antimicrobial Peptides during the Arthropod Response to Alphavirus Replication

“…The arthropod immune system consists of the RNAi pathway, as well as the Toll, Imd, and Jak-STAT signaling pathways, which result in changes in the transcriptome leading to the production of proviral and antiviral factors. Previously published microarray studies have reported many genes that are regulated in response to alpha-and flavivirus infections in Drosophila S2 cells, Aedes aegypti midguts, and whole Aedes aegypti mosquitoes (25,42,43). In the present study we identified 95 genes with significantly altered expression as a result of SINV replication in whole Drosophila.…”

West Nile Virus: Biology, Transmission, and Human Infection

“…Evidence for a transcriptomic signature of flavivirus infection was found during a comprehensive study of Aedes aegypti infected with WNV, DENV, and YFV (42). Genes involved in transcription and ion binding were found to be downregulated, and genes coding for proteases and cuticle proteins were found to be upregulated, during infection with all three viruses (42).…”

Antiviral responses of arthropod vectors: an update on recent advances

“…Recent advances in high throughput technologies, such as transcriptomics and proteomics, for pathogen-host interaction studies [25,52,96,109,117,136], as well as the publication of several vector species genomes including the mosquitoes Culex quinquefasciatus [2], Anopheles gambiae [49] and Aedes aegypti [89] and the tick Ixodes scapularis [46], have led to the discovery of immunity pathway orthologues in these species [65,105]. While there is no midge genome available to date, recent combined efforts of The Pirbright Institute and the European Bioinformatics Institute (part of the European Molecular Biology Laboratory; EBI-EMBL) have led to the first full de novo sequencing project for Culicoides sonorensis.…”