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

项目摘要/摘要 世界卫生组织警告说，由蚊媒传播的 裂谷热病毒(RVFV)。裂谷热是家畜的一种重要的人畜共患病。 传播给人，在那里它会导致从轻微到致命的一系列疾病。RVFV的意义在于 突出的是它被指定为NIAID A类病原体，并被列入世卫组织的 强调裂谷热病毒对全球卫生和经济的潜在影响。鲜为人知 关于RVFV用来感染多个物种的细胞的进入因子。我们严谨而令人信服 初步数据表明，宿主脂代谢途径中存在一种细胞表面受体，该受体可介导猪瘟病毒感染 RVFV培养的细胞。这一提议将确定RVFV中这种脂质受体蛋白的生物学意义 通过与RVFV感染相关的细胞类型的条件性基因敲除引起的小鼠疾病，包括 肝细胞、神经元和髓系细胞。我们将使用瞬时和遗传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。我们假设消除脂肪 肝脏中受体的表达将把小鼠从高度致命的感染中拯救出来。我们进一步假设 小鼠脂质受体的条件性和组织特异性基因缺失将限制与RVFV相关的 致病后果，包括肝病和脑炎。我们高度协作和协同的团队 由RVFV发病机制专家艾米·哈特曼博士(Pi)和Gaya Amarasinghe博士(Co-I)领导， 在宿主-病原体相互作用方面有专长的生物化学家和生物物理学家。本R21提案提出了一个 有机会扩大我们的合作努力，以确定RVFV-LID的生物学相关性 小鼠模型中受体的相互作用。这项提议的完成将对该领域产生很大影响，因为 这是RVFV对受体使用情况的第一次体内评估。所有试剂都是可用的，包括小鼠品系， 病毒和技术；因此，可行性很高。

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.