Mechanisms and Modifiers of Zika Virus Innate Immune Evasion

摘要 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 2015-2016年疫情蔓延至南美洲、北美、太平洋岛屿和其他地区(1-3)。 以前与由伊蚊传播的轻微或无症状感染有关，美国人 寨卡病毒的爆发与#年小头畸形症和格林-巴利综合征的较高发病率有关 怀孕期间感染的妇女的孩子。寨卡病毒有性传播和无性传播的证据 病毒加上长潜伏期继续加剧了公众对安全的担忧。同时进行实验性疫苗接种 目前正在寻求策略，目前尚无寨卡病毒感染的已知治疗方法或特定的预防措施 为前往疫区旅行的高危专业人员或个人提供治疗。最新的研究 寨卡病毒和其他黄病毒使用的分子致病机理和毒力因子揭示了一种 干扰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(干扰素)，使病毒对外源性干扰素治疗更具抵抗力，并有助于 毒力、组织穿透性和寄主嗜性。黄病毒NS5蛋白已被认为是主要的 干扰素-JAK-STAT信号的拮抗剂，登革病毒和寨卡病毒都被证明使用NS5来 激活并破坏STAT2，它是干扰素反应中必不可少的转录调节因子。而登革热病毒则使用 针对STAT2的一种特异的细胞泛素连接酶，寨卡病毒使用一种独特的机制，通过 未知的蜂窝机械(13)。寨卡病毒介导的STAT2降解和干扰素逃逸的初步研究 人类细胞为设计敏感的基于活细胞的分析系统提供了基础，以鉴定细胞 用于STAT2降解和寨卡病毒复制的组件。因为病毒宿主逃避的机制是 被假设为治疗干预的高潜在目标，提出了两个互补的目标 (目标1)确定寨卡病毒NS5介导的STAT2降解所需的细胞成分和(目标2)利用 该途径作为小分子抑制寨卡病毒复制的靶点。专注于这些最初的热门歌曲 具有一般性和机械性反筛选和低通量跟踪分析的创新实验 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 用于毒力和致病机理的调查，以提供治疗干预措施，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.