Interferon signaling inhibition by the Zika virus NS5 protein

项目摘要/摘要 寨卡病毒(ZIKV)在南美的大规模疫情已经席卷了世界 惊喜啊。在其大爆发之前，ZIKV被认为是一种低流行病毒，通过 伊蚊，并在人类中引起一些轻微的发烧疾病。然而，由于 它在美洲大陆的到来，可能与人类旅行有关，ZIKV的案例 感染呈爆炸式增长，病毒继续通过热带和亚热带传播 美洲国家。重要的是，寨卡病毒感染最近与 神经系统疾病，包括感染病毒的孕妇所生婴儿的小头畸形， 以及受感染个体中格林-巴利综合征的增加。几乎什么都不知道 关于ZIKV的分子致病机理和毒力因子。我们之前与其他人的研究 黄病毒，包括西尼罗河病毒(WVN)、登革病毒(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非凡能力 干扰素(干扰素-I)信号传递，尽管机制不同。这使得这些病毒 对干扰素-I具有抵抗力，并有助于它们的毒力和寄主取向。我们的实验室最近发现 ZIKV还有效地抑制了感染细胞中的干扰素-I信号，并发现，类似于 DENV，病毒NS5蛋白与参与干扰素-I的关键转录因子STAT2结合 信号，并以退化为目标。然而，我们的数据也表明，STAT2介导的 ZIKV NS5的降解通过与DENV NS5不同的机制进行。在 在R21的背景下，我们建议定位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复制中的STAT2降解、宿主反应诱导及其对 干扰素-I在人细胞中的抗病毒作用(目标2)。干扰素-I受损的突变型ZIKV 此R21建议书中将生成的对抗性属性将代表 进一步研究它们在体内的衰减特性及其作为活体的潜在用途 ZIKV弱毒疫苗。此外，在此R21中生成的数据对于 未来的研究将通过ZIKV如何降解STAT2来更好地了解这一机制，这可能会 结果确定了用于抗病毒开发的新靶点。

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.