Role of the novel entry factor Lrp1 in in vivo tropism and pathogenesis of Rift Valley fever virus

项目总结/摘要 世界卫生组织警告说，由蚊子传播的 裂谷热病毒（RVFV）。裂谷热是家畜的一种重要疾病， 传播给人类，在那里它会导致一系列从轻微到致命的疾病。RVFV的意义在于 它被指定为NIAID A类病原体，并被列入世界卫生组织的蓝图， 重点疾病，强调RVFV对全球健康和经济的潜在影响。知之甚少 RVFV用来感染多个物种细胞的进入因子。我们的严谨和令人信服的 初步数据确定宿主脂质代谢途径中的细胞表面受体，其介导 细胞RVFV。这一建议将确定该脂质受体蛋白在RVFV中的生物学意义 通过在与RVFV感染相关的细胞类型中的条件性敲除， 肝细胞、神经元和骨髓细胞。我们将使用瞬时的和遗传的组织特异性条件基因 使用Cre/Lox系统产生的脂质受体的敲除。我们假设， 受体在肝脏中的表达将使小鼠免于高致死性感染。我们进一步假设 小鼠中脂质受体的条件性和组织特异性基因缺失将限制RVFV相关的 致病结果，包括肝病和脑炎。我们高度协作和协同的团队 由RVFV发病机理专家Amy Hartman博士（PI）和RVFV研究专家Gaya Amarasinghe博士（Co-I）领导。 具有宿主-病原体相互作用方面的专业知识的生物化学家和生物药理学家。这份R21提案提出了一个 有机会扩大我们的合作努力，以确定RVFV-脂质的生物相关性， 受体相互作用的小鼠模型。完成本提案将对现场产生重大影响，因为 这是RVFV对受体利用的首次体内评估。所有试剂都可用，包括小鼠品系， 病毒和技术;因此，可行性高。

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.