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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

基本信息

批准号：
10188412
负责人：
Shinji Makino
金额：
$ 19.75万
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：
2020
资助国家：
美国
起止时间：
2020-06-10 至 2023-05-31
项目状态：
已结题

项目摘要

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.

裂谷热白蛉病毒（RVFV）是一种布尼亚病毒，属于NIAID A类病原体清单和CDC潜在生物恐怖主义制剂清单。RVFV引起的疾病在撒哈拉以南非洲地区流行，并可能出现爆炸性的蚊子传播的流行病，杀死羊群和牛群，造成巨大的经济损失。在人类中，RVFV感染可引起出血热、脑炎和视网膜血管炎。许多不同的蚊子，包括几种原产于北美的蚊子，都是RVFV传播的有效载体。将RVFV引入北美可能会在普通人群中引起恐慌，对牲畜的影响可能会产生毁灭性的经济影响。缺乏用于人或家畜的许可疫苗或抗RVFV试剂是非常令人担忧的。RVFV基因组由三部分组成，分别为编码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NS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; NS由抗原组正义S RNA转录的mRNA翻译而来，而N蛋白由基因组正义S RNA转录的mRNA产生。病毒复制和传播的关键步骤之一是将病毒基因组包装到病毒颗粒中，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颗粒的潜在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节是有价值的。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。我们提出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。本申请将通过表征Gn与反基因组S RNA的直接相互作用来阐明反基因组S RNA有效包装到病毒颗粒中的机制和生物学意义，鉴定病毒RNA中的Gn结合位点，并检查反基因组S RNA包装对于RVFV复制的重要性。从拟议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，总体目标是为新型抗病毒药物和疫苗的设计提供信息。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rift Valley fever virus 78kDa envelope protein attenuates virus replication in macrophage-derived cell lines and viral virulence in mice.

DOI：
10.1371/journal.pntd.0009785
发表时间：
2021-09
期刊：
PLoS neglected tropical diseases
影响因子：
3.8
作者：
Terasaki K;Kalveram B;Johnson KN;Juelich T;Smith JK;Zhang L;Freiberg AN;Makino S
通讯作者：
Makino S

Characterization of the Molecular Interactions That Govern the Packaging of Viral RNA Segments into Rift Valley Fever Phlebovirus Particles.

控制病毒 RNA 片段包装成裂谷热白蛉病毒颗粒的分子相互作用的表征。