Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor-associated protein (RAP) as critical host factors for RVFV infection. RVFV Gn directly binds to specific Lrp1 clusters and is glycosylation independent. Exogenous addition of murine RAP domain 3 (mRAP_D3) and anti-Lrp1 antibodies neutralizes RVFV infection in taxonomically diverse cell lines. Mice treated with mRAP_D3 and infected with pathogenic RVFV are protected from disease and death. A mutant mRAPD3 that binds Lrp1 weakly failed to protect from RVFV infection. Together, these data support Lrp1 as a host entry factor for RVFV infection and define a new target to limit RVFV infections.

裂谷热病毒 (RVFV) 是一种具有大流行潜力的人畜共患病病原体。RVFV 进入是由病毒糖蛋白 (Gn) 介导的，但宿主进入因素仍然不明确。我们的全基因组 CRISPR 筛选将低密度脂蛋白受体相关蛋白 1（小鼠 Lrp1/人 LRP1）、热休克蛋白 (Grp94) 和受体相关蛋白 (RAP) 确定为 RVFV 感染的关键宿主因子。RVFV Gn 直接与特定的 Lrp1 簇结合，并且不依赖糖基化。鼠 RAP 结构域 3 (mRAP _D3 ) 和抗 Lrp1 抗体的外源添加可中和分类学不同细胞系中的 RVFV 感染。用 mRAP _{D3治疗的小鼠}并感染了致病性裂谷热病毒，免受疾病和死亡的影响。与 Lrp1 弱结合的突变 mRAPD3 未能保护免受 RVFV 感染。总之，这些数据支持 Lrp1 作为 RVFV 感染的宿主进入因子，并定义了限制 RVFV 感染的新目标。