权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

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.

项目总结