ADAR1-mediated antiviral response in Zika virus (ZIKV) infection

项目摘要 作为对病毒感染的反应，宿主细胞触发先天/抗病毒免疫反应， 主要通过产生干扰素(IFN)和干扰素刺激基因(ISGs)。这些反- 病毒反应促进炎症、免疫细胞激活和病毒清除。我们最近 据报道，视网膜色素上皮(RPE)和视网膜血管或脉络膜内皮细胞 对寨卡病毒(ZIKV)感染高度许可，并通过增加 生产综合框架网络和综合服务指南。ZIKV感染的RPE的转录分析显示 作用于RNA1的腺苷脱氨酶(ADAR1)是一种强大的ISG，它能在体内发挥促肾上腺皮质激素的作用。 或通过对宿主和病毒RNA进行A-to-I编辑来实现抗病毒活性。行动的作用和机制 到目前为止，对ZIKV过程中ADAR1及相关黄病毒的研究尚不多见。我们的预赛 研究表明：1)ADAR1在转录本以及ZIKV上的蛋白水平上调 感染RPE细胞，2)ADAR1过表达减少，而ADAR1被敲除 RPE细胞中ZIKV复制增加。这些发现促使我们研究ADAR1的作用 在视网膜对ZIKV和其他黄病毒的先天免疫中。因此，这项提案的总体目标是 ADAR1抑制RPE中ZIKV复制的作用机制研究 细胞(目标1)；以及确定ADAR1消融和ADAR1过表达的后果 关于ZIKV诱导的小鼠脉络膜视网膜萎缩模型(目标2)。拟议的研究将 拓宽和深化我们对眼部ZIKV感染过程中的抗病毒反应的认识。我们的 研究还可以基于RNA编辑能力确定新的靶点和治疗方式 主人的名字。

Project Summary In response to viral infections, host cells trigger an innate/anti-viral immune response, predominantly by producing the interferons (IFNs) and IFN-stimulated genes (ISGs). These anti- viral responses promote inflammation, immune cell activation, and viral clearance. We recently reported that retinal pigment epithelium (RPE) and retinal vascular or choroidal endothelium are highly permissive to Zika virus (ZIKV) infection and elicit antiviral response with increased production of IFNs and ISGs. The transcriptomic analysis of ZIKV-infected RPE revealed the induction of adenosine deaminases acting on RNA1 (ADAR1), a potent ISG, which can exert pro- or antiviral activity by A-to-I editing of the host and viral RNA. The role and mechanisms of action of ADAR1 during ZIKV and related flaviviruses have not been studied till now. Our preliminary studies show that 1) ADAR1 is up-regulated at the transcript, as well as, protein levels upon ZIKV infection in RPE cells, and 2) ADAR1 overexpression reduced, while ADAR1 knockdown increased, ZIKV replication in RPE cells. These findings led us to investigate the role of ADAR1 in retinal innate immunity to ZIKV and other flaviviruses. Thus, the overall goal of this proposal is to determine the mechanisms of antiviral actions of ADAR1 in attenuating ZIKV replication in RPE cells (Aim 1); and to determine the consequences of ADAR1 ablation and ADAR1 overexpression on ZIKV-induced chorioretinal atrophy in a mouse model (Aim 2). The proposed studies will broaden and deepen our knowledge of the antiviral response during ocular ZIKV infection. Our studies could also identify new targets and treatment modalities based on the RNA editing ability of the host.