Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-born zoonotic bunyavirus that causes severe hemorrhagic fever and death in humans. CCHFV enters the cell via clathrin-mediated endocytosis which is dependent on its surface glycoproteins. However, the cellular receptors that are required for CCHFV entry are unknown. Here we show that the low density lipoprotein receptor (LDLR) is an entry receptor for CCHFV. Genetic knockout of LDLR impairs viral infection in various CCHFV-susceptible human, monkey and mouse cells, which is restored upon reconstitution with ectopically-expressed LDLR. Mutagenesis studies indicate that the ligand binding domain (LBD) of LDLR is necessary for CCHFV infection. LDLR binds directly to CCHFV glycoprotein Gc with high affinity, which supports virus attachment and internalization into host cells. Consistently, a soluble sLDLR–Fc fusion protein or anti-LDLR blocking antibodies impair CCHFV infection into various susceptible cells. Furthermore, genetic knockout of LDLR or administration of an LDLR blocking antibody significantly reduces viral loads, pathological effects and death following CCHFV infection in mice. Our findings suggest that LDLR is an entry receptor for CCHFV and pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever.

克里米亚-刚果出血热病毒 (CCHFV) 是最广泛的蜱传人畜共患布尼亚病毒，可导致人类严重出血热和死亡。 CCHFV 通过网格蛋白介导的内吞作用进入细胞，该内吞作用依赖于其表面糖蛋白。然而，CCHFV 进入所需的细胞受体尚不清楚。在这里，我们证明低密度脂蛋白受体（LDLR）是 CCHFV 的进入受体。 LDLR 的基因敲除会损害各种 CCHFV 易感人、猴和小鼠细胞中的病毒感染，而用异位表达的 LDLR 重建后，病毒感染会恢复。诱变研究表明 LDLR 的配体结合域 (LBD) 对于 CCHFV 感染是必需的。 LDLR 以高亲和力直接与 CCHFV 糖蛋白 Gc 结合，支持病毒附着和内化到宿主细胞中。一致地，可溶性 sLDLR-Fc 融合蛋白或抗 LDLR 阻断抗体会削弱 CCHFV 对各种易感细胞的感染。此外，对 LDLR 进行基因敲除或给予 LDLR 阻断抗体可显着降低小鼠 CCHFV 感染后的病毒载量、病理效应和死亡。我们的研究结果表明，LDLR 是 CCHFV 的进入受体，针对 LDLR 的药理学靶向可能提供预防和治疗克里米亚-刚果出血热的策略。