中国科学院Yan-Yi Wang团队近期取得重要工作进展，他们研究提出，LDLR是克里米亚-刚果出血热病毒的一种进入受体。相关研究成果2024年1月5日在线发表于《细胞研究》杂志上。

据介绍，克里米亚-刚果出血热病毒（CCHFV）是最广泛传播的蜱生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依赖于其表面糖蛋白的内吞作用进入细胞。然而，CCHFV进入所需的细胞受体尚不清楚。

研究人员发现，低密度脂蛋白受体（LDLR）是CCHFV的进入受体。LDLR的基因敲除削弱了各种CCHFV易感的人类、猴子和小鼠细胞中的病毒感染，这些细胞在用异位表达的LDLR重建后恢复。突变研究表明，LDLR的配体结合域（LBD）是CCHFV感染所必需的。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。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，LDLR的基因敲除或LDLR阻断抗体的给药显著降低了小鼠感染CCHFV后的病毒载量、病理影响和死亡。

总之，这一研究结果表明，LDLR是CCHFV的进入受体，LDLR的药理学靶向可能为预防和治疗克里米亚-刚果出血热提供一种策略。

附：英文原文

Title: LDLR is an entry receptor for Crimean-Congo hemorrhagic fever virus

Author: Xu, Zhi-Sheng, Du, Wen-Tian, Wang, Su-Yun, Wang, Mo-Yu, Yang, Yi-Ning, Li, Yu-Hui, Li, Zhen-Qi, Zhao, Li-Xin, Yang, Yan, Luo, Wei-Wei, Wang, Yan-Yi

Issue&Volume: 2024-01-05

Abstract: 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.

DOI: 10.1038/s41422-023-00917-w

Source: https://www.nature.com/articles/s41422-023-00917-w