Interactions of Emerging Bunyaviruses with Host Cells

布尼亚病毒科由300多种病毒组成，隶属于布尼亚病毒科四个属(汉坦病毒， 正本雅氏病毒、猪瘟病毒和奈罗病毒)感染人类。一些汉坦病毒和裂谷 谷热病毒(RVFV，一种细小病毒)是A类病原体，特别令人担忧。 RVFV是通过受感染的蚊子传播的，1931年在肯尼亚首次被描述，此后一直 在非洲大部分地区和阿拉伯半岛都有记载。RVFV会引起急性发烧， 有时，视网膜或肝脏并发症伴有出血症状。最近在肯尼亚爆发的一场疫情 重症患者的病死率超过20%。此外，RVFV还会造成灾难性的 家养动物的流产率很高，因此可能造成重大的经济损失。因此，它是 被美国疾控中心和美国农业部归类为重叠选择代理。也可以是 令人担忧的是一些汉坦病毒会导致汉坦病毒肺综合征(HPS)和/或 人类肾综合征出血热(HFRS)。这些由啮齿动物传播的病毒包括 辛诺布雷病毒、安第斯病毒和普玛拉病毒。RVFV和汉坦病毒是未被研究的病原体 目前还没有获得批准的疫苗或疗法。在2005年开始的MARCE的支持下， 我们发起了一项研究RVFV的努力，最近还研究了几种汉坦病毒。与同事一起工作在 美国疾病控制与预防中心和宾夕法尼亚大学，我们已经开发了一系列基因工具和功能分析 用于高通量、全基因组RNAi和化学文库筛选以识别宿主细胞 这些病毒复制和传播所需的分子和途径。重大进展 与RVFV的合作已经制作完成。通过研究几种布尼亚病毒，我们希望确定细胞途径 以及识别对该病毒家族具有独特重要性的细胞分子 特定的病毒剂。我们项目的总体目标是确定治疗干预的宿主细胞靶点。 具体来说，我们建议： 1.使用RVFV完成我们的全基因组RNAi和化学文库筛选，验证HITS和 确定作用机制。 2.开发进行全基因组RNAi和 化学图书馆筛查Sin Norbre病毒。 3.通过测试安第斯山脉和普马拉山脉来确定行动的广度。

The family Bunyaviridae consists of over 300 viruses with members of four Bunyaviridae genera (Hantavirus, Orthobunyavirus, Phlebovirus and Nairovirus) infecting humans. A number of the Hantaviruses and Rift Valley Fever virus (RVFV, a Phlebovirus) are Category A agents with RVFV being of particular concern. RVFV, which is spread by infected mosquitoes, was first described in Kenya in 1931 and has since been documented throughout much of Africa and the Arabian peninsula. RVFV causes acute fevers and, sometimes, retinal or hepatic complications with hemorrhagic symptoms. A recent outbreak in Kenya had a case-fatality rate of greater than 20% for those with severe illness. In addition, RVFV causes catastrophic abortion rates in domesticated animals, and thus can causes significant economic losses. As a result, it is categorized as an overlap select agent by both the CDC and the US Department of Agriculture. Also of concern are a number of Hantaviruses that cause hantavirus pulmonary syndrome (HPS) and/or hemorrhagic fever with renal syndrome (HFRS) in humans. Included among these rodent-borne viruses are Sin Nombre virus, Andes virus, and Puumala virus. RVFV and hantaviruses are under-studied pathogens for which there are no approved vaccines or therapeutics. With support from the MARCE beginning in 2005, we launched an effort to study RVFV and, more recently, several hantaviruses. Working with colleagues at USAMRIID, the CDC and at Penn, we have developed a series of genetic tools and functional assays that are being used in high throughput, whole genome RNAi and chemical library screens to identify host cell molecules and pathways needed for the replication and dissemination of these viruses. Significant progress with RVFV has already been made. By studying several bunyaviruses, we hope to identify cellular pathways that are common to this virus family, as well as to identify cellular molecules that are uniquely important to specific viral agents. The overall goal of our project is to identify host cell targets for therapeutic intervention. Specifically, we propose to: 1. Complete our whole genome RNAi and chemical library screens with RVFV, validate hits and determine mechanism of action. 2. Develop the genetic tools, assays and reagents needed to perform whole genome RNAi and chemical library screens for Sin Nombre virus. 3. Determine breadth of action by testing against Andes and Puumala.