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

新世界鼠媒出血热病毒(NWA)，如Jun病毒，大约有 30%的死亡率。尽管一种有效的Jun病毒疫苗减少了疾病 这种疾病的发病率、零星病例以及其他已知和新的非传染性非传染性疾病 如果没有疫苗或有效的治疗方法仍在发生。因为它们是通过气溶胶传播的， 这些A类病毒也是潜在的生物恐怖分子。我们最近表演了一场 用携带Jun糖蛋白的伪型病毒进行siRNA筛选寻找宿主基因 参与了可能成为治疗靶点的进入。我们发现了一些不是 以前与病毒感染有关，包括TRIM2，三方基序(TRIM)的成员 包括寄主对病毒感染的内在防御的知名成员的家庭。 我们证明了TRIM2是一种抗病毒进入的宿主因子。除了它们的抗病毒活性外， TRIM蛋白参与广泛的生物学功能，包括细胞增殖， 泛素化、细胞凋亡和多种人类病理。在这里，我们将调查可能的 TRIM2通过实现以下目的来限制NWA感染的新机制： 目的1：研究TRIM2对君病毒感染哪些环节的影响。 目的2：确定TRIM2是如何限制Jun病毒感染的。 目的3：确定TRIM2是否在体内抑制Jun病毒感染。 这些研究将使我们能够确定TRIM2限制的潜在独特机制 NWA感染，并将使我们能够开发关键试剂，为未来的体内研究TRIM2在 病毒感染并处于正常发育中。

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.