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：
8748204
负责人：
SUSAN R ROSS
金额：
$ 24万
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/8748204
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 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 public health relevance therapeutic target ubiquitin-protein ligase

项目摘要

New world rodent-borne hemorrhagic fever arenaviruses (NWA) such as Jun¿n virus have about a 30% mortality rate. Although an effective Jun¿n 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 Jun¿n 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 in 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 Jun¿n virus infection are affected by TRIM2. Aim 2: Determine how TRIM2 restricts Jun¿n virus infection. Aim 3: Determine if TRIM2 restricts Jun¿n 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 virus infection and in normal development.

新世界啮齿动物传播的出血性竞技病毒（NWA），例如Junân病毒虽然有效的JUN¿N病毒疫苗降低了疾病，但死亡率为30％。发病率，零星的情况以及其他已知和新颖的NWA 仍未发生疫苗或有效的治疗。因为它们是由气溶胶传输的，所以这些类别病毒病毒也是潜在的生物恐怖剂。我们最近进行了 siRNA筛选带有含有JUN¿N糖蛋白的伪型病毒以找到宿主基因参与可以用作治疗靶标的进入的进入。我们确定了许多基因以前与病毒感染有关，包括Trim2，Tripite基序的成员（TRIM）包括宿主对病毒感染的内在防御的著名成员的家庭。我们表明TRIM2是抗病毒进入宿主因子。除了它们的抗病毒活性，修剪蛋白参与广泛的生物学功能，包括细胞增殖，泛素化，凋亡和多种人类病理。在这里，我们将调查可能 TRIM2通过执行以下目的限制NWA感染的新型机制： AIM 1：表征Jun¿N病毒感染的哪些步骤受TRIM2的影响。 AIM 2：确定TRIM2如何限制JUN n病毒感染。 AIM 3：确定TRIM2是否限制了Vivo中的Jun n病毒感染。这些研究将使我们能够定义TRIM2限制的潜在独特机制 NWA感染，将使我们能够开发关键试剂，以供未来的体内TRIM2研究病毒感染和正常发育。