Indentification of Cellular Pathways Involvedin Rift Valley Fever Virus Infection

同时感染人类和家畜的流行性虫媒病毒病的出现导致了 世界范围内的重大发病率和死亡率。对于主机因素，我们知之甚少 这些病毒的复制周期，以及限制致病的先天免疫途径较少， 阻碍了抗病毒治疗的发展。病毒相关细胞因子的鉴定 复制和致病一直很困难，因为缺乏服从于基因的病毒宿主系统 放映。我们的主要研究目标是将高通量RNAi和小分子筛选用于 果蝇和哺乳动物细胞识别调节细胞和病毒因子的抑制物 发病机制，包括被病毒劫持用于复制的那些因素，以及由 对抗病毒入侵者的宿主。我们的研究将集中在裂谷热病毒(RVFV，一种 A类本亚病毒)，但将通过Marge内部的合作扩展到其他 医学上的意义。由于其未得到满足的医疗和农业需求，RVFV特别令人感兴趣，其 美国农业部鉴定为可能的农业恐怖主义毒剂，试剂的可用性和实验 系统，并因为有机会与Marce成员合作。我们以细胞为基础的 使用复制能力病毒的筛选方法能够识别能够 针对病毒复制所需的任何病毒或细胞因子。此外，我们的方法具有 通过二次分析剖析病毒复制来阐明这一要求的机制的能力 生命周期中的每一步。同时应用基因组规模的RNAi筛选抗病毒 RVFV和小分子筛查，均使用384孔板高通量筛查试验 (HTS)，应该可以更快地识别抗病毒药物的细胞靶点 这种医学上重要的病毒以及这种正在研究中的病毒的其他成员的发展 一家人。

The emergence of epidemic arboviral diseases infecting both humans and domestic animals has led to significant world-wide morbidity and mortality. Little is known about the host factors required for the replication cycles of these viruses, and less about the innate immune pathways that restrict pathogenesis, impeding the development of antiviral treatments. The identification of cellular factors involved in viral replication and pathogenesis has been difficult due to the lack of virus-host systems amenable to genetic screening. Our primary research goal is to use a high-throughput RNAi and small molecule screens in Drosophila and mammalian cells to identify inhibitors of both cellular and viral factors that regulate pathogenesis, including both those factors hijacked by the virus for replication, and those systems used by the host to combat the viral invader. Our studies will be focused on Rift Valley Fever Virus (RVFV, a Category A bunyavirus), but will be extended via collaborations within MARGE to other bunyaviruses of medical significance. RVFV is of particular interest due to its unmet medical and agricultural need, its identification by the USDA as a likely agroterrorism agent, the availability of reagents and experimental systems, and because of the opportunity to collaborate with members of the MARCE. Our cell-based screening approach using replication competent virus enables the identification of compounds or genes that target any factor¿viral or cellular¿that is required for viral replication. Furthermore, our method has the ability to elucidate the mechanism of this requirement by dissecting viral replication with secondary assays against each step in the lifecycle. The simultaneous application of genome-scale RNAi screens against RVFV and small molecule screens, both using a 384 well plate-based high throughput screening assay (HTS) that we have developed, should lead to more rapid identification of cellular targets for antiviral drug development for this medically important virus, as well as for other members of this under-studied virus family.