Mechanisms and Modifiers of Zika Virus Innate Immune Evasion

总结 寨卡病毒是一种黄病毒，于 1947 年在乌干达首次分离出来，并在 1947 年享誉国际。 2015-2016年疫情蔓延至南美、北美、太平洋岛屿及其他地区(1-3)。 此前曾与伊蚊传播的轻度或无症状感染有关，美国 寨卡病毒的爆发与小头畸形和吉兰巴利综合征的发病率增加有关 妇女在怀孕期间感染的孩子。寨卡病毒性传播和无性传播的证据 病毒加上潜伏期长，继续加剧公共安全担忧。实验性疫苗接种时 正在采取策略，目前尚无治疗寨卡病毒感染的已知方法或具体的预防措施 为高危专业人士或前往受影响地区的个人提供治疗。最近的研究 寨卡病毒和其他黄病毒使用的分子发病机制和毒力因子揭示了 破坏或逃避先天抗病毒免疫反应的一般能力，主要是由 I 型和 III 型干扰素 (IFN)，使病毒对外源性干扰素治疗更具抵抗力，并有助于 毒力、组织穿透性和宿主向性。黄病毒 NS5 蛋白已被认为是主要的 NS5 是 IFN-JAK-STAT 信号传导的拮抗剂，登革热病毒和寨卡病毒均已被证明使用 NS5 参与并破坏 STAT2（IFN 反应中重要的转录调节因子）。虽然登革热病毒使用 寨卡病毒使用一种特定的细胞泛素连接酶来靶向 STAT2，它使用一种独特的机制介导 未知的细胞机制 (13)。寨卡介导的 STAT2 降解和 IFN 逃避的初步研究 人类细胞为设计灵敏的活细胞检测系统以识别细胞提供了基础 用于 STAT2 降解和寨卡病毒复制的组件。由于病毒宿主逃避的机制是 假设是治疗干预的高潜力目标，提出了两个互补的目标 （目标 1）确定 Zika NS5 介导的 STAT2 降解所需的细胞成分和（目标 2）利用 将此通路作为小分子抑制寨卡病毒复制的靶标。关注这些的最初点击 具有一般和机械反筛选以及低通量后续分析的创新实验 将揭示寨卡病毒介导的干扰素逃避所需的缺失机制，提供细胞靶点 用于毒力和发病机制的研究，为治疗干预提供信息，并确定新的线索 寨卡病毒抗病毒化合物。

Summary Zika virus is a flavivirus that was first isolated in Uganda in 1947, and gained international notoriety during the 2015-2016 epidemic that spread to South America, North America, Pacific islands, and beyond (1-3). Previously associated with a mild or asymptomatic infection transmitted by Aedes mosquitos, the American Zika virus outbreak was associated with a greater incidence of microcephaly and Guillain Barré syndrome in the children of women infected during pregnancy. Evidence for both sexual and asexual transmission of Zika virus coupled with long latency periods continue to fuel public safety concerns. While experimental vaccination strategies are being pursued, there are no known cures for Zika virus infection or specific prophylactic treatments available for high risk professionals or individuals traveling to afflicted regions. Recent studies of molecular pathogenesis and virulence factors used by Zika virus and other flaviviruses have uncovered a general ability to disrupt or evade innate antiviral immune responses, primarily those mediated by type I and type III interferon (IFN), making the viruses more resistant to exogenous IFN therapy and contributing to virulence, tissue penetration, and host tropism. The flavivirus NS5 protein has been recognized as a primary antagonist of IFN-JAK-STAT signaling, and both Dengue virus and Zika virus have been shown to use NS5 to engage and destroy STAT2, an essential transcription regulator in the IFN response. While Dengue virus uses a specific cellular ubiquitin ligase enzyme to target STAT2, Zika virus uses a distinct mechanism mediated by unknown cellular machinery (13). Preliminary studies of Zika-mediated STAT2 degradation and IFN evasion in human cells provided a foundation for the design of sensitive living cell-based assay systems to identify cellular components used for STAT2 degradation and Zika virus replication. As mechanisms of virus host evasion are hypothesized to be high potential targets for therapeutic intervention, two complementary aims are proposed to (Aim 1) identify the cellular components required Zika NS5-mediated STAT2 degradation and (Aim 2) exploit this pathway as a target for small molecule inhibition of Zika replication. Focusing initial hits from these innovative experiments with general and mechanistic counter-screening and low-throughput follow-up analysis will reveal missing mechanistic machinery needed for Zika virus-mediated IFN evasion, provide cellular targets for investigations of virulence and pathogenesis to inform therapeutic interventions, and identify new leads for Zika virus antiviral compounds.