Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
PLoS Pathog. 2011 Sep;7(9):e1002189. doi: 10.1371/journal.ppat.1002189. Epub 2011 Sep 1.
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.
西尼罗河病毒（WNV）、登革热病毒（DENV）和黄热病病毒（YFV）是（重新）出现的、通过蚊子传播的黄病毒，它们在全球范围内引起人类疾病和死亡。蚊子基因表达的改变在个别黄病毒感染中是常见的，但其独特性却知之甚少。在这里，我们展示了 DENV、WNV 或 YFV 感染期间，埃及伊蚊转录组随时间的微阵列分析。我们鉴定了 203 个蚊子基因，它们在感染三种黄病毒之一时的上调倍数≥5（DUR），202 个基因的下调倍数≥10（DDR）。比较分析表明，在感染的第 1 天，20 个 DUR 基因和 15 个 DDR 基因的表达谱在三种黄病毒之间非常相似，这表明黄病毒感染存在潜在的保守转录组特征。生物信息学分析显示，包括离子结合、运输、代谢过程和肽酶活性在内的多种细胞过程中的基因表达发生了变化。我们还证明了病毒调节的基因表达是组织特异性的。几种病毒下调基因的过表达降低了蚊细胞和埃及伊蚊中的 WNV 感染。其中，一种蛹皮蛋白被证明可以结合 WNV 包膜蛋白，从而在体外抑制感染，并预防致命的 WNV 脑炎在小鼠中。这项工作提供了一个广泛的控制蚊子中黄病毒感染的靶标列表，这些靶标也可用于开发针对多种黄病毒的广泛预防和治疗措施。
