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.

Rift Valley Fever Phlebovirus（RVFV）是Bunyavirus，属于NIAID类别的病原体清单和潜在的生物恐怖剂的CDC清单。 RVFV引起了撒哈拉以南非洲特有的疾病，可以在爆炸性的，蚊子传播的流行病中出现，该流行病会使绵羊和牛的牛群消失，从而造成巨大的经济损失。在人类中，RVFV感染可能导致出血热，脑炎和视网膜血管炎。许多不同的蚊子，包括北美本地的几种物种，是RVFV传播的合格向量。将RVFV引入北美可能会引起普通人群的恐慌，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持牌疫苗或抗RVFV试剂的可用性。 RVFV携带三方，单链，负敏感的RNA基因组，包括编码L蛋白的L RNA，编码两个主要包膜糖蛋白的M RNA，GN和GC，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Ambi-Sense策略进行基因表达。 NSS从从抗原敏感的S RNA转录的mRNA翻译，而N蛋白是由从基因组义S RNA转录的mRNA产生的。病毒复制和传播的基本步骤之一是病毒基因组包装到病毒颗粒中，但是，RVFV和其他Bunyavirues中病毒RNA包装的机制在很大程度上是未知的。洞悉控制病毒RNA基因组中RVFV颗粒包装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理的调节而言是有价值的。这些知识对于可以抑制感染性病毒产生或发育活疫苗菌株的抗病毒药物的开发也至关重要。我们建议GN与病毒RNA片段的直接相互作用是影响病毒RNA在RVFV颗粒中的包装效率的主要因素。本应用将通过表征GN与抗原组S RNA的直接相互作用，确定病毒RNA中的GN结合位点的直接相互作用，并检查抗原S RNA包装在RVFV重复中的重要性，从而阐明抗原S RNA有效包装到病毒颗粒中的机制和生物学意义。从拟议的研究中获得的数据将阐明在RVFV和其他BUNYAVIRES中驱动病毒RNA包装的基本机制，其总体目的是为新型抗病毒药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。