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.