Pathological Implications of Repression of Cellular RNA Decay by Zika Virus

寨卡病毒抑制细胞 RNA 衰变的病理学意义

• 批准号: 9298165
• 负责人: Jeffrey Wilusz
• 金额: $ 22.24万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298165
• 关键词: 3' Untranslated Regions; Address; Antiviral Agents; Area; Biological; Cell Communication; Cells; Central America; Congenital Abnormality; Cytopathology; Data; Defense Mechanisms; Development; Disease; Double-Stranded RNA; Enzymes; Exonuclease; Exoribonucleases; Fetal Tissues; Flavivirus; Foundations; Gene Expression; Generations; Goals; Infection; Insecta; International; Investigation; Knowledge; Laboratories; Lead; Mediating; Messenger RNA; Modeling; Molecular; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Play; Porifera; Pregnant Women; Proteins; RNA; RNA Decay; RNA Interference; RNA Viruses; RNA-Binding Proteins; Repression; Risk; Role; Sequence Alignment; South America; Structure; Syndrome; Testing; Time; Transcript; Untranslated RNA; Vaccine Production; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Work; Zika Virus; attenuation; base; cell type; design; drug development; enzyme structure; in utero; insight; mRNA Decay; mRNA Expression; mRNA Stability; mutant; novel; novel strategies; pathogen; public health emergency; viral RNA; virus host interaction; virus pathogenesis

PROJECT SUMMARY / ABSTRACT Zika virus is an emerging flavivirus that presents a significant risk to pregnant women and is associated with Guillian-Barre syndrome. Why the virus elicits these unforeseen pathologies is unclear, but is undoubtedly related to unique aspects of Zika virus-host interactions – a highly understudied area of investigation to date. Previous work from our laboratory has demonstrated that RNAs from other insect-borne flaviviruses contain a highly structured segment in their 3' UTR that stalls and represses the cellular exoribonuclease Xrn1. Repression of this major cellular RNA decay enzyme causes significant dysregulation of global cellular gene expression, changes that are likely very relevant to virus-induced cytopathology and pathogenesis. The first goal of this project is to demonstrate the stalling and repression of Xrn1 by Zika virus RNAs that we hypothesize should occur based on modeling with the RNAs of other flaviviruses. Importantly, we will then analyze the implications that Xrn1 repression has on Zika virus infection of cell types that are biologically relevant to fetal tissues that are particularly sensitive to virus infection in utero. Second, we will explore the possible functions of the non-coding ~400 base RNA (sfRNA) that is generated by Xrn 1 stalling and accumulates to high levels during infection. This study will for the first time explore the roles of the Zika virus 3' non-coding RNA region in virus-host interactions. We hypothesize that the Zika sfRNA likely accumulates to high levels in infected cells and may serve as a sponge to disrupt the function and/or usurp the activity of key cellular RNA binding proteins. These data should provide foundational insights for understanding Zika virus pathogenesis as well as identify novel targets for antiviral drug development or virus attenuation for vaccine production.

项目摘要/摘要 寨卡病毒是一种新出现的黄病毒，对孕妇构成重大风险，并与 格林-巴利综合征。这种病毒为什么会引起这些不可预见的病理尚不清楚，但毫无疑问 与寨卡病毒-宿主相互作用的独特方面有关--这是迄今为止研究严重不足的一个调查领域。 我们实验室以前的工作已经证明，来自其他昆虫传播的黄病毒的RNA包含一个 在它们的3‘非编码区中高度结构化的片段，它停滞并抑制细胞外切核酸酶Xrn1。 抑制这种主要的细胞RNA衰变酶导致全球细胞基因的显著失调 表达，这种变化很可能与病毒诱导的细胞病理学和发病机制非常相关。第一 这个项目的目标是演示寨卡病毒RNA对Xrn1的停滞和抑制 假设应该发生在与其他黄病毒的RNA建模的基础上。重要的是，届时我们将 分析Xrn1抑制对寨卡病毒生物学类型感染的影响 与子宫内对病毒感染特别敏感的胎儿组织有关。第二，我们将探索 Xrn 1停滞产生的非编码~400碱基RNA(SfRNA)的可能功能 在感染期间积聚到高水平。这项研究将首次探索寨卡病毒的作用。 病毒-宿主相互作用中的非编码RNA区域。我们假设寨卡病毒sfRNA很可能会累积到 感染细胞中的高水平，可能作为海绵破坏KEY的功能和/或篡夺KEY的活性 细胞RNA结合蛋白。这些数据应该为理解寨卡病毒提供基础性的见解 发病机制以及确定抗病毒药物开发或疫苗病毒减毒的新靶点 制作。