Mechanisms and Modifiers of Zika Virus Innate Immune Evasion

总结 寨卡病毒是一种黄病毒，于1947年首次在乌干达分离出来，并在2009年获得国际恶名。 2015-2016年的流行病蔓延到南美洲，北美洲，太平洋岛屿和其他地区（1-3）。 这名美国人先前与由伊蚊传播的轻度或无症状感染有关， 寨卡病毒爆发与小头畸形和格林巴利综合征的发病率较高有关， 怀孕期间受感染的妇女的子女。寨卡病毒性传播和无性传播的证据 病毒加上长潜伏期继续加剧公众安全问题。虽然实验性疫苗接种 寨卡病毒感染的治疗方法目前还没有明确的治疗方法， 为前往患病地区的高风险专业人员或个人提供治疗。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已经揭示了一种 破坏或逃避先天性抗病毒免疫应答的一般能力，主要是由I型和 III型干扰素（IFN），使病毒对外源性IFN治疗更具抵抗力，并有助于 毒力、组织渗透性和寄主向性。黄病毒NS 5蛋白已被认为是一种主要的 NS 5是IFN-JAK-STAT信号传导的拮抗剂，登革病毒和寨卡病毒都显示出使用NS 5来 参与并破坏STAT 2，这是IFN应答中的一种重要转录调节因子。而登革热病毒利用 Zika病毒是一种靶向STAT 2的特异性细胞泛素连接酶， 未知的细胞机器（13）。寨卡病毒介导的STAT 2降解和IFN逃逸的初步研究 人细胞为设计灵敏的基于活细胞的测定系统提供了基础， 用于STAT 2降解和寨卡病毒复制的组分。由于病毒逃避宿主的机制是 假设是治疗干预的高潜力靶点，提出了两个互补的目标， (Aim 1）鉴定寨卡病毒NS 5介导的STAT 2降解所需的细胞组分，并（目的2）利用 该途径作为小分子抑制寨卡病毒复制的靶点。集中这些人的初步打击 创新的实验与一般和机械的反筛选和低通量的后续分析 将揭示寨卡病毒介导的IFN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调查，为治疗干预提供信息，并确定 寨卡病毒治疗

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.