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TRIM2, a novel host factor that restricts New World Arenavirus infection

TRIM2，一种限制新世界沙粒病毒感染的新型宿主因子

基本信息

批准号：
8852547
负责人：
SUSAN R ROSS
金额：
$ 20万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8852547
关键词：
Aerosols Affect Anti-Retroviral Agents Antiviral Agents Apoptosis Arenavirus Arenavirus Infections Argentina Biological Assay Biological Process Bioterrorism Boxing C-terminal Categories Cell Culture Techniques Cell Proliferation Cells Data Dendritic Cells Development Disease Family Future Genes Glycoproteins Goals Health Human Human Pathology Immune response Incidence Infection Integration Host Factors Junin virus Knockout Mice Mediating Modeling Mus Pathway interactions Pharmaceutical Preparations Production Protein Family Proteins RNA Interference RNA Viruses Reagent Rodent Role Small Interfering RNA Specificity TRIM Motif Tacaribe Complex Viruses Testing Therapeutic Vaccines Viral Viral Hemorrhagic Fevers Viral Physiology Virion Virus Virus Diseases Work in vivo macrophage member mortality mouse model novel prevent therapeutic target ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): New world rodent-borne hemorrhagic fever arenaviruses (NWA) such as Junin virus have about a 30% mortality rate. Although an effective Junin virus vaccine has decreased disease incidence, sporadic cases of this as well as the other known and novel NWAs for which there are no vaccines or effective therapeutics still occur. Because they are transmitted by aerosols, these Category A arenaviruses are also potential bioterrorism agents. We recently performed a siRNA screen with pseudotyped viruses bearing the Junin glycoprotein to find host genes involved in entry that could serve as therapeutic targets. We identified a number of genes not previously implicated in virus infection, including TRIM2, a member of the tripartite motif (TRIM) family that includes well-known members of the host's intrinsic defense against viral infections. We showed that TRIM2 is an anti-viral entry host factor. In addition to their antiviral activity, TRIM proteins are involved i a wide range of biological functions including cell proliferation, ubiquitinylation, apoptosis and a variety of human pathologies. Here we will investigate the likely novel mechanism by which TRIM2 restricts NWA infection by carrying out the following aims: Aim 1: Characterize which steps of Junin virus infection are affected by TRIM2. Aim 2: Determine how TRIM2 restricts Junin virus infection. Aim 3: Determine if TRIM2 restricts Junin virus infection in vivo. These studies will allow us to define the potentially unique mechanism by which TRIM2 restricts NWA infection and will allow us to develop critical reagents for future in vivo studies of TRIM2 in virs infection and in normal development.

描述（申请人提供）：新世界啮齿动物传播的出血热沙粒病毒（NWA），例如胡宁病毒，死亡率约为30%。尽管有效的胡宁病毒疫苗已降低了疾病发病率，但这种情况以及其他已知和新型 NWA 尚无疫苗或有效治疗方法的散发病例仍然发生。由于这些 A 类沙粒病毒通过气溶胶传播，因此也是潜在的生物恐怖分子。我们最近对带有胡宁糖蛋白的假型病毒进行了 siRNA 筛选，以找到参与进入的宿主基因，这些基因可以作为治疗靶点。我们鉴定了许多以前与病毒感染无关的基因，包括 TRIM2，它是三重基序 (TRIM) 家族的成员，该家族包括宿主针对病毒感染的内在防御的众所周知的成员。我们证明 TRIM2 是一种抗病毒进入宿主因子。除了抗病毒活性外，TRIM 蛋白还参与多种生物学功能，包括细胞增殖、泛素化、细胞凋亡和多种人类病理学。在这里，我们将通过实现以下目标来研究 TRIM2 限制 NWA 感染的可能新机制：目标 1：表征胡宁病毒感染的哪些步骤受 TRIM2 影响。目标 2：确定 TRIM2 如何限制胡宁病毒感染。目标 3：确定 TRIM2 是否限制体内胡宁病毒感染。这些研究将使我们能够定义 TRIM2 限制 NWA 感染的潜在独特机制，并使我们能够开发关键试剂，用于未来 TRIM2 在病毒感染和正常发育中的体内研究。