New Paradigm for Host and Viral Gene Regulation by MERS Coronavirus nsp1

MERS 冠状病毒 nsp1 宿主和病毒基因调控的新范式

基本信息

批准号：
9189963
负责人：
Shinji Makino
金额：
$ 4.66万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189963
关键词：
5&apos Untranslated Regions Acute Kidney Failure Animals Area Binding Biological Process Camels Case Fatality Rates Case Study Cell Nucleus Cells Chiroptera Chronic Complex Coronavirus Coughing Country Cytoplasm Data Down-Regulation Dromedaries Equilibrium Europe Exhibits Fever Foundations Gene Expression Gene Expression Regulation Genes Genetic Translation Genome Health Human Immune Response Genes Immunosuppression Infection Interferon Type I Interferons International Knowledge Mediating Medical Messenger RNA Middle East Middle East Respiratory Syndrome Coronavirus Molecular Murine hepatitis virus Mutate Nonstructural Protein Northern Africa Pathogenesis Pathogenicity Pathway interactions Patients Persons Play Pneumonia Polyproteins Process Production Property Protein Biosynthesis Proteins Public Health RNA RNA chemical synthesis Recruitment Activity Regulation Reporting Respiratory Failure Role SARS coronavirus Saudi Arabia Severe Acute Respiratory Syndrome Site Testing Translations Transmissible gastroenteritis virus Viral Viral Genes Viral Genome Viral Proteins Virulence Virulence Factors Virus Virus Replication Zoonoses endonuclease mRNA Decay mRNA Stability mRNA Transcript Degradation messenger ribonucleoprotein mutant novel transcriptome viral RNA

项目摘要

DESCRIPTION (provided by applicant): Middle East respiratory syndrome coronavirus (MCoV) emerged in Saudi Arabia in 2012 and has been disseminated into other countries in the Middle East, North Africa and Europe. Although MERS is most probably a zoonosis, MCoV can spread person-to-person. MCoV infection causes fever, cough and pneumonia leading to respiratory failure, and the reported case fatality is ~50%. Little is known about the mechanisms of MCoV's high virulence and pathogenesis. Coronaviruses (CoVs) carry a single-stranded, positive-sense RNA genome of ~30 kb. Immediately after infection, the translation of the viral genome produces two large polyproteins that are processed into 15 or 16 mature nonstructural proteins (nsp1-nsp16), most of which are involved in viral RNA synthesis, while some have other biological functions. Nsp1 protein of various CoVs inhibits host gene expression. Viral proteins that inhibit host gene expression are often major virulence factors, and, hence, CoV nsp1 proteins most probably play a critical role in CoV pathogenesis. Indeed, mouse hepatitis virus nsp1 is a major virulence factor, and SARS-CoV (SCoV) nsp1 inhibits the production of type I interferon and interferon-stimulated genes in infected cells. Nsp1 proteins of different CoVs use divergent strategies to exert host gene expression suppression; by binding to the 40S ribosomal subunit, SCoV nsp1 inhibits mRNA translation and induces endonucleolytic mRNA cleavage, while nsp1 of transmissible gastroenteritis virus does not induce mRNA cleavage, yet suppresses translation without binding to the 40S ribosomal subunits. Our data that MCoV nsp1 inhibited translation of host mRNAs and promoted mRNA cleavage without binding to the 40S subunits and other experimental results led us to hypothesize that MCoV nsp1 suppresses host gene expression by using mechanisms that have not been described in any viral proteins. This application aims to delineate the mechanisms of MCoV nsp1-induced translation inhibition and mRNA cleavage. We will also clarify the strategy that allows robust viral gene expression in MCoV-infected cells under conditions of nsp1- induced translation inhibition. The proposed studies will provide a foundation for understanding the modulation of host gene expression by MCoV and expand our knowledge of viral pathogenicity at the molecular level.

描述（由申请人提供）：中东呼吸综合征冠状病毒（MCoV）于 2012 年在沙特阿拉伯出现，并已传播到中东、北非和欧洲的其他国家。 MCoV 感染会导致发烧、咳嗽和肺炎，导致呼吸衰竭，据报道，MCoV 的高毒力和致死率约为 50%。冠状病毒 (CoV) 携带约 30 kb 的单链正义 RNA 基因组，感染后病毒基因组立即翻译产生两个大的多蛋白，这些多蛋白被加工成 15 或 16 个成熟的非结构蛋白 (nsp1-nsp16)。），其中大部分参与病毒RNA合成，而一些具有其他生物学功能的各种冠状病毒的Nsp1蛋白则抑制宿主基因表达，而抑制宿主基因表达的病毒蛋白往往是主要的。事实上，小鼠肝炎病毒 nsp1 是主要的毒力因子，并且 SARS-CoV (SCoV) nsp1 抑制 I 型干扰素和干扰素的产生。受感染细胞中的 Nsp1 蛋白使用不同的策略通过与 40S 核糖体亚基 SCoV 结合来抑制宿主基因表达； nsp1 抑制 mRNA 翻译并诱导核酸内切 mRNA 裂解，而传染性胃肠炎病毒的 nsp1 不诱导 mRNA 裂解，但在不与 40S 核糖体亚基结合的情况下抑制翻译。我们的数据表明，MCoV nsp1 抑制宿主 mRNA 的翻译并促进 mRNA 裂解，但不与 40S 核糖体亚基结合。 40S 亚基和其他实验结果使我们发现 MCoV nsp1 通过使用抑制宿主基因表达本申请旨在描述 MCoV nsp1 诱导的翻译抑制和 mRNA 裂解的机制，我们还将阐明在 nsp1 条件下允许 MCoV 感染细胞中病毒基因稳健表达的策略。 - 诱导翻译抑制。拟议的研究将为理解 MCoV 对宿主基因表达的调节奠定基础，并在分子水平上扩展我们对病毒致病性的了解。