Mechanisms and Modifiers of Zika Virus Innate Immune Evasion

寨卡病毒先天免疫逃避的机制和修饰因素

基本信息

批准号：
10056954
负责人：
CURT M HORVATH
金额：
$ 23.23万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-20 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056954
关键词：
Address Aedes American Antiviral Agents Antiviral Response Antiviral Therapy Automobile Driving Biological Assay Cells Cellular Assay Chemicals Child Coupled Culicidae Dengue Virus Disease Outbreaks Enzymes Epidemic Flavivirus Foundations Future Genes Genetic Genetic Transcription Goals Guillain-Barré Syndrome Human Immune Evasion Immune response Immune system Immunosuppression Incidence Individual Infection Interferon Suppression Interferons International Intervention Investigation Knowledge Libraries Life Cycle Stages Mediating Medical Microcephaly Microscopic Molecular Molecular Analysis Molecular Probes North America Pacific Islands Pathogenesis Pathogenicity Pathway interactions Penetration Pregnancy Prophylactic treatment Proteins Public Health Reproducibility Research Research Project Grants Resistance Risk STAT2 gene Safety Signal Transduction South America System Techniques Therapeutic Therapeutic Intervention Tissues Travel Tropism Uganda Virulence Virulence Factors Virus Virus Replication Woman ZIKA ZIKV disease ZIKV infection Zika Virus antiviral immunity asexual base cellular targeting design experimental study follow-up high risk high throughput screening innovation insight interferon therapy monocyte novel novel therapeutics pathogenic virus response screening small molecule success targeted treatment transmission process ubiquitin ligase vaccination strategy vector mosquito virology

项目摘要

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.

概括寨卡病毒是一种黄病毒，于1947年首次在乌干达孤立，并在此期间闻名 2015 - 2016年流行病，传播到南美，北美，太平洋岛屿以及以上（1-3）。以前与埃德斯蚊子传播的轻度或无症状感染有关，美国在怀孕期间感染的妇女的孩子。寨卡的性和无性传播的证据病毒加上长期潜伏期，继续引起公共安全问题。而实验疫苗接种正在采用策略，没有已知的寨卡病毒感染或特定预防治疗方法可用于高风险专业人员或前往受苦地区的个人。最近的研究寨卡病毒和其他黄病毒所使用的分子发病机理和病毒因子已经发现了一般破坏或逃避先天抗病毒免疫调查的能力，主要由I型介导的人和 III型干扰素（IFN），使病毒对外源性IFN疗法具有更抗性病毒，组织渗透和宿主乳房。黄病毒NS5蛋白已被认为是主要的 IFN-JAK-STAT信号的拮抗剂以及登革热病毒和Zika病毒均已证明使用NS5 参与并破坏IFN响应中的基本转录调节器STAT2。而登革热病毒使用特定的细胞泛素连接酶针对靶标STAT2，寨卡病毒使用由未知的蜂窝机械（13）。 Zika介导的STAT2降解和IFN进化的初步研究人类细胞为设计敏感的活细胞测定系统设计提供了基础，以识别细胞用于STAT2降解和Zika病毒复制的组件。由于病毒宿主环境的机制是据称是治疗干预的高潜在目标，提出了两个完整的目标（AIM 1）确定所需的细胞成分Zika NS5介导的STAT2降解和（AIM 2）利用该途径是小分子抑制Zika复制的靶标。从这些关注初始命中一般和机械反向筛查和低通量随访分析的创新实验将揭示寨卡病毒介导的IFN所需的缺失的机械机械，提供细胞靶用于病毒和发病机理的投资，以告知治疗干预措施，并确定新的潜在客户寨卡病毒抗病毒化合物。