Interferon signaling inhibition by the Zika virus NS5 protein

寨卡病毒 NS5 蛋白抑制干扰素信号传导

• 批准号: 9265245
• 负责人: Adolfo Garcia-Sastre
• 金额: $ 25.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265245
• 关键词: Aedes; Africa; American; Americas; Amino Acids; Animal Model; Animals; Antiviral Agents; Antiviral Response; Area; Asia; Attenuated Live Virus Vaccine; Binding; Binding Proteins; Biology; Cavia; Cells; Collaborations; Complication; Country; Culicidae; Data; Dengue Virus; Development; Disease Outbreaks; Epidemic; Ferrets; Fever; Flavivirus; French Polynesia; Future; Guillain-Barré Syndrome; Hamsters; Human; Immune response; Impairment; Individual; Innate Immune Response; Interferon Type I; Interferons; Knowledge; Letters; Maps; Mediating; Microcephaly; Molecular; Mothers; Mus; Mutation; Mutation Analysis; Pathogenesis; Property; Proteins; Puerto Rico; Reporting; Resistance; STAT2 gene; Signal Transduction; South America; Travel; Tropism; United States National Institutes of Health; Viral; Virulence; Virulence Factors; Virus; Virus Diseases; Virus Replication; West Nile virus; Yellow fever virus; Zika Virus; Zika virus vaccine; attenuation; cytokine; experimental study; in vivo; mutant; nervous system disorder; novel; pregnant; public health emergency; transcription factor; vector

PROJECT SUMMARY/ABSTRACT The large epidemic outbreak of Zika virus (ZIKV) in South America has taken the world by surprise. Prior to its large outbreak, ZIKV was considered a low prevalent virus, transmitted by the Aedes mosquito, and causing a few cases of mild febrile illness in humans. However, since its arrival in the American continent, probably related to human travel, the cases of ZIKV infections have exploded and the virus continues to spread through tropical and subtropical countries in the Americas. Importantly, ZIKV infections have recently been associated with neurological disorders, including microcephaly in babies born from infected pregnant mothers, and increases in Guillain-Barré syndrome in infected individuals. Practically nothing is known about the molecular pathogenesis and virulence factors of ZIKV. Our previous studies with other flaviviruses, including West Nile virus (WVN), dengue virus (DENV) and yellow fever virus (YFV) have revealed their remarkable abilities to inhibit innate immune responses by targeting type I interferon (IFN-I) signaling, although by different mechanisms. This makes these viruses more resistant to IFN-I and contributes to their virulence and host tropism. Our lab has recently found that ZIKV also efficiently inhibits IFN-I signaling in infected cells and identified that, similar to DENV, the viral NS5 protein binds to STAT2, a critical transcription factor involved in IFN-I signaling, and targets it to degradation. However, our data also indicate that STAT2-mediated degradation by ZIKV NS5 takes place by a mechanism different from that of DENV NS5. In the context of this R21 we propose to map the domains and amino acid residues in both ZIKV NS5 and STAT2 responsible for their interactions (Aim 1) and to study the impact of NS5-mediated STAT2 degradation in ZIKV replication, host response induction and in its sensitivity to the antiviral action of IFN-I in human cells (Aim 2). The mutant ZIKVs with impaired IFN-I antagonistic properties that will be generated in this R21 proposal will represent the basis for additional studies to investigate their attenuation properties in vivo and their potential use as live attenuated vaccines against ZIKV. In addition, data generated in this R21 will be critical for future studies to better understand the mechanism by how ZIKV degrades STAT2, which might result in the identification of novel targets for antiviral development.

项目概要/摘要 南美洲寨卡病毒（ZIKV）大流行已席卷全球 令人惊讶的是，在大规模爆发之前，寨卡病毒被认为是一种流行率较低的病毒，通过以下途径传播。 伊蚊，并导致人类出现一些轻度发热性疾病。 它到达美洲大陆，可能与人类旅行有关，ZIKV 病例 感染激增，病毒继续在热带和亚热带传播 重要的是，ZIKV 感染最近与美洲国家有关。 神经系统疾病，包括受感染的怀孕母亲所生婴儿的小头畸形， 感染者吉兰-巴利综合征的增加几乎一无所知。 关于 ZIKV 的分子发病机制和毒力因素。 黄病毒，包括西尼罗河病毒（WVN）、登革热病毒（DENV）和黄热病病毒（YFV） 揭示了它们通过靶向 I 型来抑制先天免疫反应的卓越能力 干扰素（IFN-I）信号传导，尽管通过不同的机制，这使得这些病毒更加容易。 我们的实验室最近发现，它对 IFN-I 具有抗性，并有助于其毒力和宿主向性。 ZIKV 还可以有效抑制受感染细胞中的 IFN-I 信号传导，并发现，与 DENV，病毒 NS5 蛋白与 STAT2 结合，STAT2 是 IFN-I 中涉及的关键转录因子 然而，我们的数据还表明 STAT2 介导。 ZIKV NS5 的降解机制与 DENV NS5 不同。 在此 R21 的背景下，我们建议绘制 ZIKV NS5 中的结构域和氨基酸残基 和 STAT2 负责它们的相互作用（目标 1）并研究 NS5 介导的影响 ZIKV 复制、宿主反应诱导及其对 ZIKV 的敏感性中的 STAT2 降解 IFN-I 在人类细胞中的抗病毒作用（目标 2） IFN-I 受损的突变型 ZIKV。 R21 提案中将产生的对抗特性将代表 其他研究旨在调查它们的体内衰减特性及其作为活体的潜在用途 此外，R21 中生成的数据对于 ZIKV 减毒疫苗至关重要。 未来的研究可以更好地理解 ZIKV 如何降解 STAT2 的机制，这可能 从而确定抗病毒开发的新靶点。