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.

项目摘要/摘要 南美洲寨卡病毒（ZIKV）的大量流行病席卷了世界 惊喜。在大规模爆发之前，Zikv被认为是一种低流行病毒，由 埃德斯蚊子，并引起了人类的一些轻度发热疾病。但是，自从 它到达美国大陆，可能与人类旅行有关的ZIKV案件 感染已经爆炸，病毒继续通过热带和亚热带传播 美洲国家。重要的是，ZIKV感染最近与 神经系统疾病，包括受感染孕妇出生的婴儿的小头畸形， 并增加了受感染个体中的Guillain-Barré综合征。几乎什么都没知道 关于ZIKV的分子发病机理和病毒因子。我们以前与其他的研究 黄病毒，包括西尼罗病毒（WVN），登革热病毒（DENV）和黄热病病毒（YFV） 已经揭示了他们通过瞄准I型抑制先天免疫反应的非凡能力 干扰素（IFN-I）信号传导，尽管是通过不同的机制。这使这些病毒更多 对IFN-I的抗药性并有助于其病毒和宿主的偏向主义。我们的实验室最近发现 该ZIKV还有效地抑制了感染细胞中的IFN-I信号传导，并确定了类似于 DENV，病毒NS5蛋白与STAT2结合，STAT2是IFN-I涉及的关键转录因子 信号传导，并将其靶向降解。但是，我们的数据还表明STAT2介导 ZIKV NS5的降解是通过与DENV NS5不同的机制进行的。在 R21的上下文我们建议在两个ZIKV NS5中绘制域和氨基酸残基 STAT2负责其相互作用（AIM 1）并研究NS5介导的影响 ZIKV复制中的STAT2降解，宿主响应诱导以及其对 IFN-I在人类细胞中的抗病毒作用（AIM 2）。 IFN-I受损的突变ZIKVS 在本R21提案中将生成的对抗特性将代表 其他研究以调查其体内的衰减特性及其潜在用途 对针对Zikv的疫苗减弱。此外，此R21中生成的数据对于 未来的研究以更好地了解ZIKV如何降低STAT2的机制，这可能 导致鉴定抗病毒发育的新靶标。