Flavivirus induces and antagonizes antiviral RNA interference in both mammals and mosquitoes
Flavivirus induces and antagonizes antiviral RNA interference in both mammals and mosquitoes
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黄病毒在哺乳动物和蚊子中诱导并拮抗抗病毒 RNA 干扰
DOI：
10.1126/sciadv.aax7989
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发表时间：
2020-02-01
期刊：
影响因子：
13.6
通讯作者：
Zhou, Xi
中科院分区：
文献类型：
--
作者：
Qiu, Yang;Xu, Yan-Peng;Zhou, Xi
黄病毒如登革热使用相同的策略来逃避哺乳动物和蚊子中基于RNAi的内在抗病毒防御。蚊媒黄病毒感染哺乳动物和蚊子。RNA干扰（RNAi）已被证明是蚊子中的抗黄病毒机制;然而，黄病毒是否以及如何在哺乳动物中诱导和拮抗RNAi介导的抗病毒免疫仍是未知的。我们发现登革病毒2型（DENV-2）的非结构蛋白NS 2A作为RNAi（VSR）的病毒抑制因子。当NS 2A介导的RNAi抑制被禁用时，所得突变体DENV 2诱导分化的哺乳动物细胞中大量DENV 2衍生的siRNA的Dicer依赖性产生。VSR失活的DENV 2在蚊子和哺乳动物细胞中以及在通过RNAi缺陷拯救的小鼠中显示出严重的复制缺陷。此外，多种黄病毒的NS 2A在体外和在两种生物体中的病毒感染期间充当VSR。总的来说，我们的研究结果表明，抗病毒RNAi可以由黄病毒诱导，而黄病毒使用NS 2A作为真正的VSR来逃避哺乳动物和蚊子中的RNAi，突出了RNAi在黄病毒载体-宿主生命周期中的重要性。
Flaviviruses such as dengue use the same strategy to evade RNAi-based intrinsic antiviral defenses in both mammals and mosquitoes. Mosquito-borne flaviviruses infect both mammals and mosquitoes. RNA interference (RNAi) has been demonstrated as an anti-flavivirus mechanism in mosquitoes; however, whether and how flaviviruses induce and antagonize RNAi-mediated antiviral immunity in mammals remains unknown. We show that the nonstructural protein NS2A of dengue virus-2 (DENV2) act as a viral suppressor of RNAi (VSR). When NS2A-mediated RNAi suppression was disabled, the resulting mutant DENV2 induced Dicer-dependent production of abundant DENV2-derived siRNAs in differentiated mammalian cells. VSR-disabled DENV2 showed severe replication defects in mosquito and mammalian cells and in mice that were rescued by RNAi deficiency. Moreover, NS2As of multiple flaviviruses act as VSRs in vitro and during viral infection in both organisms. Overall, our findings demonstrate that antiviral RNAi can be induced by flavivirus, while flavivirus uses NS2A as a bona fide VSR to evade RNAi in mammals and mosquitoes, highlighting the importance of RNAi in flaviviral vector-host life cycles.