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.

项目总结/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-巴利综合征为什么病毒会引发这些不可预见的病理尚不清楚，但毫无疑问， 寨卡病毒与宿主相互作用的独特方面有关-这是迄今为止研究得非常不足的一个领域。 我们实验室以前的工作已经证明，来自其他虫媒黄病毒的RNA含有一个 在它们的3' UTR中的高度结构化的区段，其阻止和抑制细胞核糖核酸外切酶Xrn 1。 这种主要的细胞RNA降解酶的抑制导致整体细胞基因的显著失调， 表达，可能与病毒诱导的细胞病理学和发病机制非常相关的变化。第一 该项目的目标是证明Zika病毒RNA对Xrn 1的停滞和抑制， 这一假设应该基于其他黄病毒RNA的建模。重要的是，我们将 分析Xrn 1抑制对寨卡病毒感染生物学上 与对子宫内病毒感染特别敏感的胎儿组织相关。第二，我们将探讨 由Xrn 1失速产生的非编码~400碱基RNA（sfRNA）的可能功能， 在感染期间积累到高水平。这项研究将首次探索寨卡病毒3'的作用。 非编码RNA区在病毒与宿主相互作用中的作用。我们假设寨卡病毒sfRNA可能积累到 感染细胞中的高水平，并可作为海绵破坏功能和/或篡夺关键的活性， 细胞RNA结合蛋白。这些数据应该为了解寨卡病毒提供基础见解 致病机理以及鉴定用于抗病毒药物开发或疫苗病毒减毒的新靶点 生产