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

描述(申请人提供)：新世界啮齿动物传播的出血热病毒(NWA)，如Junin病毒，死亡率约为30%。尽管一种有效的Junin病毒疫苗降低了发病率，但仍有零星的此类病例以及其他已知和新的无疫苗或有效疗法的非霍奇金淋巴瘤病例发生。由于它们是通过气溶胶传播的，这些A类ARENA病毒也是潜在的生物恐怖分子。我们最近对携带Junin糖蛋白的伪型病毒进行了siRNA筛选，以寻找参与进入的宿主基因，这些基因可以作为治疗靶点。我们发现了一些以前与病毒感染无关的基因，包括TRIM2，它是三方基序(TRIM)家族的成员，包括宿主抵御病毒感染的固有防御的已知成员。我们证明了TRIM2是一种抗病毒进入的宿主因子。除了抗病毒活性外，TRIM蛋白还参与了广泛的生物学功能，包括细胞增殖、泛素化、细胞凋亡和各种人类病理。在这里，我们将通过实现以下目的来研究TRIM2限制NWA感染的可能的新机制：目的1：鉴定TRIM2影响Junin病毒感染的哪些步骤。目的2：确定TRIM2是如何限制Junin病毒感染的。目的3：确定TRIM2是否在体内限制Junin病毒的感染。这些研究将使我们能够确定TRIM2限制NWA感染的潜在独特机制，并将使我们能够为未来在VIRS感染和正常发育中进行TRIM2的体内研究开发关键试剂。

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.