Mechanism of viral RNP recognition by the envelope glycoprotein and its role in RNA segment packaging in Rift Valley Fever phlebovirus

裂谷热白蛉病毒包膜糖蛋白识别病毒RNP的机制及其在RNA片段包装中的作用

• 批准号: 10057583
• 负责人: Shinji Makino
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-10 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057583
• 关键词: Africa; Africa South of the Sahara; Agriculture; Animals; Antiviral Agents; Antiviral Response; Attenuated Live Virus Vaccine; Binding Sites; Biological; Biological Assay; Bioterrorism; Bunyaviridae; Categories; Cattle; Cells; Centers for Disease Control and Prevention (U.S.); Code; Country; Culicidae; Cytoplasm; Cytoplasmic Tail; Data; Development; Disease; Disease Outbreaks; Domestic Animals; Economics; Elements; Encephalitis; Endemic Diseases; Epidemic; Evolution; Gene Expression; General Population; Genome; Genomics; Genus Phlebovirus; Glycoproteins; Goals; Golgi Apparatus; Human; Immune response; Infection; Innate Immune Response; Interferons; Knowledge; Life Cycle Stages; Livestock; Mediating; Messenger RNA; Movement; National Institute of Allergy and Infectious Disease; Nonstructural Protein; North America; Nucleocapsid Proteins; Panic; Patients; Population; Production; Proteins; Public Health; RNA; RNA Viruses; RNA chemical synthesis; RNA-Directed RNA Polymerase; Reagent; Regulation; Research; Retina; Retinal Vasculitis; Ribonucleoproteins; Rift Valley Fever; Role; Ruminants; Sheep; Signal Transduction; Structure; System; Testing; Translating; Vaccines; Viral; Viral Genome; Viral Hemorrhagic Fevers; Viral Packaging; Viral Pathogenesis; Virion; Virulence Factors; Virus; Virus Assembly; Virus Replication; Visual impairment; design; economic impact; genomic RNA; insight; macula; mosquito-borne; mutant; novel; particle; pathogen; programs; transmission process; vector; viral RNA; viral genomics

Rift Valley fever Phlebovirus (RVFV), a bunyavirus, belongs to the NIAID Category A list of pathogens and the CDC list of potential bioterrorism agents. RVFV causes a disease that is endemic in sub-Saharan Africa and can emerge in explosive, mosquito-borne epidemics that decimate herds of sheep and cattle, resulting in enormous economic losses. In humans, RVFV infection may cause hemorrhagic fever, encephalitis, and retinal vasculitis. Many different mosquitoes, including several species native to North America, are competent vectors for RVFV transmission. The introduction of RVFV into North America would likely cause panic in the general population, and the effects on livestock could have a devastating economic impact. The lack of availability of licensed vaccines or anti-RVFV reagents for use in humans or domestic animals is of great concern. RVFV carries a tripartite, single-stranded, negative-sense RNA genome, including L RNA encoding L protein, M RNA encoding two major envelope glycoproteins, Gn and Gc, and S RNA encoding N and NSs. NSs is the major virulence factor that efficiently suppresses host antiviral responses. The S RNA uses an ambi-sense strategy for gene expression; NSs is translated from the mRNA that is transcribed from the antigenomic-sense S RNA, whereas N protein is produced from the mRNA that is transcribed from the genomic-sense S RNA. One of the essential steps in virus replication and dissemination is the packaging of viral genome into virus particles, however, the mechanisms of viral RNA packaging in RVFV and other bunyaviruses are largely unknown. Insight into the underlying rules and mechanisms that govern the packaging of viral RNA genome into RVFV particles is valuable for understanding the regulation of virus replication, virus evolution, and the pathogenesis of the virus. This knowledge is also critical for the development of antiviral drugs that can inhibit infectious virus production or for the development of a live- attenuated vaccine strain. We propose that a direct interaction of Gn with the viral RNA segments is the primary factor that influences the packaging efficiencies of viral RNAs into RVFV particles. The present application will clarify the mechanism and biological significance of efficient packaging of antigenomic S RNA into virus particles by characterizing the direct interaction of Gn with antigenomic S RNA, identify the Gn- binding sites in viral RNAs, and examine the importance of antigenomic S RNA packaging for RVFV replication. The data obtained from the proposed studies will clarify the fundamental mechanisms that drive viral RNA packaging in RVFV and other bunyaviruses, with the overall goal of informing the design of novel antivirals and vaccines.

裂谷热静脉病毒（RVFV）是一种布尼亚病毒，属于NIAID的a类病原体清单和CDC的潜在生物恐怖主义制剂清单。裂谷热病毒是撒哈拉以南非洲地区的一种地方性疾病，可通过蚊子传播的爆炸性流行病出现，导致大批牛羊死亡，造成巨大的经济损失。在人类中，裂谷热病毒感染可引起出血热、脑炎和视网膜血管炎。许多不同的蚊子，包括北美本土的几种蚊子，都是裂谷热病毒传播的有效媒介。将裂谷热病毒引入北美可能会引起一般人群的恐慌，对牲畜的影响可能会产生毁灭性的经济影响。缺乏用于人类或家畜的许可疫苗或抗裂谷热病毒试剂是非常令人关切的。RVFV携带一个三边单链负义RNA基因组，包括编码L蛋白的L RNA，编码两种主要包膜糖蛋白Gn和Gc的M RNA，以及编码N和NSs的S RNA。NSs是有效抑制宿主抗病毒反应的主要毒力因子。S RNA使用双义策略进行基因表达；NSs由反基因组意义上的S RNA转录的mRNA翻译而成，而N蛋白则由基因组意义上的S RNA转录的mRNA产生。病毒复制和传播的重要步骤之一是将病毒基因组包装成病毒颗粒，然而，RVFV和其他布尼亚病毒中病毒RNA包装的机制在很大程度上是未知的。深入了解病毒RNA基因组包装成RVFV颗粒的基本规则和机制，对于理解病毒复制、病毒进化和病毒发病机制的调控具有重要价值。这一知识对于开发能够抑制传染性病毒产生的抗病毒药物或开发减毒活疫苗株也至关重要。我们认为Gn与病毒RNA片段的直接相互作用是影响病毒RNA包装成RVFV颗粒效率的主要因素。本应用将通过表征Gn与抗基因组S RNA的直接相互作用，阐明抗基因组S RNA高效包装成病毒颗粒的机制和生物学意义，确定病毒RNA中Gn的结合位点，并检验抗基因组S RNA包装对RVFV复制的重要性。从拟议的研究中获得的数据将阐明驱动RVFV和其他布尼亚病毒中病毒RNA包装的基本机制，其总体目标是为新型抗病毒药物和疫苗的设计提供信息。