Department of Biological Sciences, The George Washington University, Washington, DC 20052, USA.
NYU Langone Health, Alexandria Center for Life Science, New York, NY 10016, USA.
Dis Model Mech. 2020 Apr 30;13(4):dmm040816. doi: 10.1242/dmm.040816.
To gain a comprehensive view of the changes in host gene expression underlying Zika virus (ZIKV) pathogenesis, we performed whole-genome RNA sequencing (RNA-seq) of ZIKV-infected adult flies. RNA-seq analysis revealed that ZIKV infection alters several and diverse biological processes, including stress, locomotion, lipid metabolism, imaginal disc morphogenesis and regulation of JAK/STAT signaling. To explore the interaction between ZIKV infection and JAK/STAT signaling regulation, we generated genetic constructs overexpressing ZIKV-specific non-structural proteins NS2A, NS2B, NS4A and NS4B. We found that ectopic expression of non-structural proteins in the developing eye significantly restricts growth of the larval and adult eye and correlates with considerable repression of the JAK/STAT reporter, At the cellular level, eye growth defects are associated with reduced rate of proliferation without affecting the overall rate of apoptosis. In addition, ZIKV NS4A genetically interacts with the JAK/STAT signaling components; co-expression of along with the dominant-negative form of or results in aggravated reduction in eye size, while co-expression of in (also known as ) mutant background partially rescues the -induced eye overgrowth phenotype. The function of ZIKV NS4A in regulating growth is maintained in the wing, where ZIKV overexpression in the pouch domain results in reduced growth linked with diminished expression of Notch targets, Wingless (Wg) and Cut, and the Notch reporter, Thus, our study provides evidence that ZIKV infection in results in restricted growth of the developing eye and wing, wherein eye phenotype is induced through regulation of JAK/STAT signaling, whereas restricted wing growth is induced through regulation of Notch signaling. The interaction of ZIKV non-structural proteins with the conserved host signaling pathways further advance our understanding of ZIKV-induced pathogenesis.This article has an associated First Person interview with the first author of the paper.
为全面了解寨卡病毒（ZIKV）发病机制中宿主基因表达的变化，我们对感染 ZIKV 的成年果蝇进行了全基因组 RNA 测序（RNA-seq）。RNA-seq 分析显示，ZIKV 感染改变了几个不同的生物学过程，包括应激、运动、脂质代谢、胚盘形态发生和 JAK/STAT 信号转导的调节。为了探索 ZIKV 感染与 JAK/STAT 信号转导调节之间的相互作用，我们构建了过表达 ZIKV 特异性非结构蛋白 NS2A、NS2B、NS4A 和 NS4B 的遗传构建体。我们发现，非结构蛋白在发育中的 眼中的异位表达显著限制了幼虫和成虫眼的生长，并与 JAK/STAT 报告基因的显著抑制相关。在细胞水平上，眼生长缺陷与增殖率降低有关，而不影响总体凋亡率。此外，ZIKV NS4A 与 JAK/STAT 信号转导成分发生遗传相互作用；与显性负形式的 或 共表达导致眼大小的严重减小，而在 （也称为 ）突变背景下与 共表达部分挽救了 -诱导的眼过度生长表型。ZIKV NS4A 在调节生长中的功能在翅膀中得到维持，在口袋域中过表达 ZIKV 导致生长减少，与 Notch 靶基因 Wingless (Wg) 和 Cut 以及 Notch 报告基因 的表达减少有关。因此，我们的研究提供了证据，表明 ZIKV 在 中的感染导致发育中的眼和翅膀生长受限，其中眼表型是通过调节 JAK/STAT 信号转导诱导的，而翅膀生长受限是通过调节 Notch 信号转导诱导的。ZIKV 非结构蛋白与保守的宿主信号通路的相互作用进一步加深了我们对 ZIKV 诱导的发病机制的理解。本文有一篇与该论文第一作者的第一人称访谈。
