Molecular determinants of virulent arenavirus infection in hosts

宿主强毒沙粒病毒感染的分子决定因素

基本信息

批准号：
8651859
负责人：
YUYING LIANG
金额：
$ 41.86万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651859
关键词：
Acute Animal Model Animals Antiviral Agents Arenaviridae Arenavirus Arenavirus Infections Biological Assay Biology C-terminal CDK6-associated protein p18 Cavia Cells Clinical Containment Development Disease Disease Outcome Family Glycoproteins Human Immune response In Vitro Infection Junin virus Knowledge Laboratories Lassa Fever Lassa fever virus Lassa virus Lead Mediating Missense Mutation Modeling Molecular Molecular Genetics Morbidity - disease rate Nucleoproteins Pathogenesis Pathway interactions Pichinde virus Polymerase Proteins RNA chemical synthesis Replicon Reporter Role Site Specificity Subfamily lentivirinae Symptoms System Testing Vaccines Viral Viral Genome Viral Hemorrhagic Fevers Viral Proteins Virulence Virulence Factors Virulent Virus Diseases Virus Replication Work base combat effective therapy mortality novel therapeutic intervention particle positional cloning protein protein interaction public health relevance therapeutic target tool viral RNA virus genetics

项目摘要

DESCRIPTION (provided by applicant): Arenaviruses such as Lassa fever virus (LASV) can cause acute viral hemorrhagic fever disease in humans, to which there is no vaccine or effective treatment. Studies on basic biology, virulent mechanism, and pathogenesis of LASV are significantly hindered, partly due to the strict requirement for BSL-4 containment to work with this select agent and the lack of infectious clones. A small animal model for Lassa fever - guinea pig infected with a non-pathogenic Pichinde virus (PICV) within the same Arenaviridae family - has shown many similarities in the clinical and histopathological findings to lethal human Lassa fever infections. We have recently developed the infectious clones for two closely related PICV strains that show opposing disease outcomes in guinea pigs. In addition, we have developed safe and convenient systems to characterize arenavirus envelope glycoprotein (GPC)-mediated cell entry and LASV viral RNA synthesis in vitro. Based on our preliminary results, we hypothesize that the GPC-mediated cell entry and the polymerase protein L- dependent viral RNA synthesis represent two major virulence mechanisms of arenavirus. We propose to utilize the many molecular, genetic, and animal systems that are available in our laboratory to characterize the molecular determinants of virulent arenavirus infection in the infected hosts and to explore the virulence mechanisms of the GPC and L proteins at molecular level. Specifically, we wish to (1) characterize the molecular determinants for virulent infection in a guinea pig model of arenavirus hemorrhagic fever, (2) characterize the molecular mechanism of arenavirus GPC protein in cell entry pathways, (3) characterize the molecular mechanism of LASV L protein in viral RNA synthesis, viral replication, and virulence. These studies may lead to identification of potential therapeutic targets against Lassa fever and other arenavirus hemorrhagic fever diseases.

描述（由申请人提供）：沙粒病毒如拉沙热病毒（LASV）可引起人类急性病毒性出血热病，目前尚无疫苗或有效治疗方法。对 LASV 的基础生物学、毒力机制和发病机制的研究受到严重阻碍，部分原因是 BSL-4 与这种选择的病原体配合使用的严格要求以及缺乏感染性克隆。拉沙热小动物模型——感染同一沙粒病毒科非致病性皮钦德病毒（PICV）的豚鼠——在临床和组织病理学结果上显示出与致命的人类拉沙热感染的许多相似之处。我们最近开发了两种密切相关的 PICV 毒株的感染性克隆，它们在豚鼠中表现出相反的疾病结果。此外，我们还开发了安全便捷的系统来表征沙粒病毒包膜糖蛋白 (GPC) 介导的细胞进入和体外 LASV 病毒 RNA 合成。根据我们的初步结果，我们假设 GPC 介导的细胞进入和聚合酶蛋白 L 依赖性病毒 RNA 合成代表了沙粒病毒的两种主要毒力机制。我们建议利用我们实验室现有的许多分子、遗传和动物系统来表征受感染宿主中毒力沙粒病毒感染的分子决定因素，并在分子水平上探索 GPC 和 L 蛋白的毒力机制。具体来说，我们希望（1）表征沙粒病毒出血热豚鼠模型中毒力感染的分子决定因素，（2）表征沙粒病毒GPC蛋白在细胞进入途径中的分子机制，（3）表征LASV的分子机制L蛋白参与病毒RNA合成、病毒复制和毒力。这些研究可能会导致确定针对拉沙热和其他沙粒病毒出血热疾病的潜在治疗靶点。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I-like receptor-dependent interferon production.

致病性而非非致病性沙粒病毒的 Z 蛋白抑制 RIG-I 样受体依赖性干扰素产生。

DOI：
发表时间：
2015-03
期刊：
影响因子：
0
作者：
Xing, Junji;Ly, Hinh;Liang, Yuying
通讯作者：
Liang, Yuying

Immune evasion mechanisms of arenaviruses.

沙粒病毒的免疫逃避机制。

DOI：
发表时间：
2015-12-01
期刊：
影响因子：
0
作者：
Ly, Hinh;Liang, Yuying
通讯作者：
Liang, Yuying

High-resolution structure of the N-terminal endonuclease domain of the Lassa virus L polymerase in complex with magnesium ions.

拉沙病毒 L 聚合酶 N 端核酸内切酶结构域与镁离子复合物的高分辨率结构。

DOI：
发表时间：
2014
期刊：
影响因子：
3.7
作者：
Wallat, Gregor D;Huang, Qinfeng;Wang, Wenjian;Dong, Haohao;Ly, Hinh;Liang, Yuying;Dong, Changjiang
通讯作者：
Dong, Changjiang

Structures of arenaviral nucleoproteins with triphosphate dsRNA reveal a unique mechanism of immune suppression.

沙粒病毒核蛋白与三磷酸 dsRNA 的结构揭示了独特的免疫抑制机制。

DOI：
发表时间：
2013-06-07
期刊：
影响因子：
0
作者：
Jiang, Xue;Huang, Qinfeng;Wang, Wenjian;Dong, Haohao;Ly, Hinh;Liang, Yuying;Dong, Changjiang
通讯作者：
Dong, Changjiang

In vitro and in vivo characterizations of pichinde viral nucleoprotein exoribonuclease functions.

pichinde 病毒核蛋白外切核糖核酸酶功能的体外和体内表征。

DOI：
发表时间：
2015-07
期刊：
影响因子：
0
作者：
Huang, Qinfeng;Shao, Junjie;Lan, Shuiyun;Zhou, Yanqin;Xing, Junji;Dong, Changjiang;Liang, Yuying;Ly, Hinh
通讯作者：
Ly, Hinh