PROJECT SUMMARY/ABSTRACT The World Health Organization warns of a pending public health emergency caused by mosquito-borne Rift Valley fever virus (RVFV). RVF is an important disease of domesticated livestock that is zoonotically transmitted to people, where it causes a spectrum of illness from mild to lethal. The significance of RVFV is highlighted by its designation as a NIAID Category A pathogen and its inclusion on the WHO's Blueprint of Priority Diseases, emphasizing the potential impact of RVFV on the global health and economy. Little is known about the entry factors that RVFV uses to infect cells from multiple species. Our rigorous and convincing preliminary data identify a cell surface receptor in the host lipid metabolism pathway that mediates infection of cells by RVFV. This proposal will determine the biological significance of this lipid receptor protein in RVFV disease in mice through conditional knockouts in cell types that are relevant to RVFV infection, including hepatocytes, neurons, and myeloid cells. We will use transient and genetic tissue-specific conditional gene knockouts of the lipid receptor generated using the Cre/Lox system. We hypothesize that eliminating lipid receptor expression in the liver will rescue mice from an otherwise highly lethal infection. We further hypothesize that conditional and tissue-specific gene deletions of the lipid receptor in mice will limit RVFV-associated pathogenic outcomes, including hepatic disease and encephalitis. Our highly collaborative and synergistic team is led by Dr. Amy Hartman (PI), an expert in the pathogenesis of RVFV, and by Dr. Gaya Amarasinghe (Co-I), a biochemist and biophysicist with expertise in host-pathogen interactions. This R21 proposal presents an opportunity to expand upon our collaborative efforts to determine the biological relevance of the RVFV-lipid receptor interaction in the mouse model. Completion of this proposal will have high impact on the field because it is the first in vivo assessment of receptor usage by RVFV. All reagents are available including mouse strains, viruses, and techniques; thus, the feasibility is high.