Regulation of RNA sensing and viral restriction by RNA structures

RNA 结构对 RNA 传感和病毒限制的调节

基本信息

批准号：
10667802
负责人：
Jennifer Lynn Hyde
金额：
$ 42.52万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667802
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Affect Alphavirus Alphavirus Infections Animals Attenuated Biochemical Brain Cells Cellular Tropism Complement Culicidae Development Disease Disease Outbreaks Double-Stranded RNA Encephalitis Epidemic Equus caballus Evolution Future Genes Genetic Genetic Transcription Genome Growth Health Human Human papillomavirus 16 E1 protein Immune Evasion Immune response Immunity In Vitro Infection Innate Immune Response Integration Host Factors Interferon Activation Interferons Licensing Macrophage Mediating Modality Molecular Mus Myeloid Cells Nature Pathogenesis Pathogenicity Periodicals Phenotype Play Process Production RNA RNA Sequences RNA Stability RNA Viruses RNA chemical synthesis RNA-Binding Proteins Regulation Role Shapes Sindbis Virus Structure Testing Therapeutic Tissues Translations Untranslated Regions Vaccines Variant Venezuelan Equine Encephalitis Virus Viral Viral Genome Viral Pathogenesis Viral Proteins Virulent Virus Virus Diseases Virus Inhibitors Virus Replication Work arthropod-borne draining lymph node enzootic epizootic fitness foot immune activation in vivo insight mosquito-borne mouse model mutant nonhuman primate novel pathogenic virus prevent recruit response single cell sequencing structural determinants therapeutic RNA tissue tropism viral RNA viral transmission

3&apos Untranslated Regions 5&apos Untranslated Regions Affect Alphavirus Alphavirus Infections Animals Attenuated Biochemical Brain Cells Cellular Tropism Complement Culicidae Development Disease Disease Outbreaks Double-Stranded RNA Encephalitis Epidemic Equus caballus Evolution Future Genes Genetic Genetic Transcription Genome Growth Health Human Human papillomavirus 16 E1 protein Immune Evasion Immune response Immunity In Vitro Infection Innate Immune Response Integration Host Factors Interferon Activation Interferons Licensing Macrophage Mediating Modality Molecular Mus Myeloid Cells Nature Pathogenesis Pathogenicity Periodicals Phenotype Play Process Production RNA RNA Sequences RNA Stability RNA Viruses RNA chemical synthesis RNA-Binding Proteins Regulation Role Shapes Sindbis Virus Structure Testing Therapeutic Tissues Translations Untranslated Regions Vaccines Variant Venezuelan Equine Encephalitis Virus Viral Viral Genome Viral Pathogenesis Viral Proteins Virulent Virus Virus Diseases Virus Inhibitors Virus Replication Work arthropod-borne draining lymph node enzootic epizootic fitness foot immune activation in vivo insight mosquito-borne mouse model mutant nonhuman primate novel pathogenic virus prevent recruit response single cell sequencing structural determinants therapeutic RNA tissue tropism viral RNA viral transmission

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项目摘要

PROJECT SUMMARY Venezuelan equine encephalitis virus (VEEV) is a single-stranded positive-sense RNA virus transmitted by mosquitoes and is responsible for periodic epizootic/epidemic outbreaks of encephalitis in both horses and humans. The innate and interferon (IFN) responses are critical barriers for preventing the replication and spread of many viral pathogens including alphaviruses such as VEEV. As a result, viruses have evolved diverse mechanisms to inhibit or escape the innate immune response as well as antiviral effectors such as IFN-stimulated genes (ISGs). RNA structures are known to regulate basic viral processes (e.g. viral RNA transcription and translation), however, the role that viral RNA structure plays in shaping innate immune responses to viruses is understudied. We have previously shown that alphaviruses encode stable structures within their 5’-untranslated region (5’-UTR) that are critical for antagonizing IFIT1, an ISG important in restriction of non-self RNA. We have also shown that RNA structures in the 3’-UTR are important in modulating recognition of viral RNA by IFIT2. Recently we have shown that RNA structures in the 3’-UTR and E1 modulate replication of virulent and avirulent VEEV in macrophages, which are important targets of VEEV infection in vivo. The broad objectives of this proposal are to: 1) delineate E1 RNA structural determinants in virulent and avirulent VEEV that regulate macrophage replication, 2) define how E1 structural determinants recruit RBPs to the viral genome and the impact of this on host innate immune responses, 3) Define how macrophage replication fitness contributes to the differential pathogenesis in vivo of VEEV encoding virulent and avirulent RNA structures, and 4) Define how macrophage replication fitness shapes innate immune responses in vivo. Findings from these studies will provide key insight into novel mechanisms of VEEV pathogenesis and emergence of pathogenic variants. This will have broad implications for our understanding of viral emergence and development of RNA-based therapeutics.

项目摘要委内瑞拉马脑炎病毒（VEEV）是一种单链阳性RNA病毒，该病毒通过蚊子，负责两种马匹和人类。先天和干扰素（IFN）的反应是防止复制和传播的关键障碍在许多病毒病原体中，包括VEEV等α病毒。结果，病毒发展了潜水员抑制或逃脱先天免疫响应以及抗病毒作用（例如IFN刺激）的机制基因（ISG）。已知RNA结构调节基本病毒过程（例如，病毒RNA转录和但是，翻译），然而，病毒RNA结构在塑造对病毒的先天免疫反应中所起的作用是研究了。我们以前已经表明，α-藻类在其5'-无翻译中编码稳定的结构对于拮抗IFIT1至关重要的区域（5'-UTR），ISG对于限制非自身RNA的重要性很重要。我们有还表明，3'-UTR中的RNA结构对于通过IFIT2调节对病毒RNA的识别很重要。最近，我们表明3'-UTR和E1中的RNA结构是有毒和无毒的复制巨噬细胞中的VEEV是体内VEEV感染的重要靶标。这个广泛的对象提案是：1）在调节的有毒和无动于衷的VEEV中描述E1 RNA结构确定剂巨噬细胞的复制，2）定义E1结构决定者如何将RBP募集到病毒基因组和这对宿主先天免疫反应的影响，3）定义巨噬细胞复制适应性如何有助于 VEEV编码有毒和无毒的RNA结构的体内差异发病机理，4）定义如何定义巨噬细胞复制适应性在体内塑造先天免疫反应。这些研究的发现将提供对VEEV发病机理的新机制和致病性变异的出现的关键见解。这将有我们对基于RNA的治疗的病毒出现和发展的理解的广泛意义。