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

• 批准号: 7889110
• 负责人: YUYING LIANG
• 金额: $ 43.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7889110
• 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

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. PUBLIC HEALTH RELEVANCE: Infection by Lassa fever virus or several other arenaviruses can lead to hemorrhagic fever (HF) diseases in humans, for which there is no vaccine (with the exception of Junin virus) or effective antiviral treatment. A related Pichinde virus in the same viral family is non-pathogenic in humans but causes distinct disease symptoms in guinea pigs that are similar to arenavirus HF in humans. We propose here to study the molecular mechanisms by which some arenaviruses can cause virulent infections in the hosts. These studies may lead to the development of effective treatments against the deadly arenavirus HF in humans.

描述（由申请方提供）：沙粒病毒如拉沙热病毒（LASV）可引起人类急性病毒性出血热疾病，目前尚无疫苗或有效治疗方法。LASV的基础生物学、毒力机制和致病机理的研究受到严重阻碍，部分原因是BSL-4遏制剂与这种选择剂一起工作的严格要求和感染性克隆的缺乏。拉沙热的小动物模型-感染同一沙粒病毒科的非致病性皮钦德病毒（PICV）的豚鼠-在临床和组织病理学发现方面与致命的人类拉沙热感染有许多相似之处。我们最近开发了两种密切相关的PICV毒株的感染性克隆，这两种毒株在豚鼠中显示出相反的疾病结果。此外，我们已经开发了安全和方便的系统来表征沙粒病毒包膜糖蛋白（GPC）介导的细胞进入和LASV病毒RNA合成的体外。基于我们的初步结果，我们假设GPC介导的细胞进入和聚合酶蛋白L依赖的病毒RNA合成代表沙粒病毒的两个主要毒力机制。我们建议利用许多分子，遗传，和动物系统，在我们的实验室中可用的特征的分子决定因素的强毒沙粒病毒感染的感染宿主，并探讨在分子水平上的GPC和L蛋白的毒力机制。具体而言，我们希望（1）表征沙粒病毒出血热豚鼠模型中强毒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 L蛋白在病毒RNA合成、病毒复制和毒力中的分子机制。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。 公共卫生相关性：拉沙热病毒或其他几种沙粒病毒的感染可导致人类的出血热（HF）疾病，对此没有疫苗（朱宁病毒除外）或有效的抗病毒治疗。同一病毒家族中的一种相关皮钦德病毒对人类无致病性，但在豚鼠中引起与人类沙粒病毒HF相似的独特疾病症状。我们建议在这里研究的分子机制，其中一些沙粒病毒可以引起宿主的毒性感染。这些研究可能导致开发针对人类致命沙粒病毒HF的有效治疗方法。