近日，美国华盛顿大学医学院教授Michael S. Diamond及其小组的研究发现多个LDLR家族成员作为黄热病病毒的进入受体。相关论文于2025年10月29日发表于国际顶尖学术期刊《自然》杂志上。

通过表面蛋白靶向CRISPR-Cas9筛选，研究人员确定了低密度脂蛋白受体（LDLR）家族成员LRP4作为YFV的候选进入受体。LRP4的基因消融会损害细胞对YFV的感染，反过来，LRP4的互补或异位表达会增加感染。YFV抗原复合体中的相关病毒主题也显示LRP4依赖性感染。LRP4通过LDLR A型（LA）结构域结合YFV包膜蛋白的结构域III促进YFV进入细胞。可溶性LRP4-Fc诱饵受体在细胞培养中中和YFV感染，并降低体内病毒负荷。

当课题组人员观察到LRP4缺陷细胞中残留的YFV感染时，课题组人员评估了其他LDLR家族成员是否促进了YFV的进入。该方法鉴定了LRP1和VLDLR是细胞培养中YFV感染的附加受体。LRP1-Fc、LRP4-Fc和VLDLR-Fc诱饵可以保护小鼠免受YFV的攻击，LRP1-Fc诱饵可以抑制人肝细胞移植小鼠的YFV感染和肝脏发病。原代人肝细胞培养中LRP1的遗传缺陷也导致YFV感染减少。他们的发现确定了多个LDLR家族成员在YFV进入、感染和发病机制中的作用，这对多种新出现的正黄病毒主题的受体主题和对策开发具有重要意义。

据介绍，黄热病病毒（原黄病毒的原型）的感染可引起人类发热综合征，并可发展为肝功能衰竭、出血和死亡。尽管经过几十年的研究，YFV的进入受体仍不清楚。

附：英文原文

Title: Multiple LDLR family members act as entry receptors for yellow fever virus

Author: Chong, Zhenlu, Hui, Sean, Qiu, Xueer, Palakurty, Sathvik, Sariol, Alan, Kaszuba, Tomasz, Nguyen, Michael N., Li, Pengfei, Raju, Saravanan, Hall, Paige D., Nelson, Christopher A., Baltazar-Perez, Israel, Price, David A., Rothlauf, Paul W., Crowe, James E., Whelan, Sean P. J., Leung, Daisy W., Amarasinghe, Gaya K., Bailey, Adam L., Fremont, Daved H., Diamond, Michael S.

Issue&Volume: 2025-10-29

Abstract: Infection by yellow fever virus (YFV), the prototype Orthoflavivirus, induces a febrile syndrome in humans that can progress to liver failure, haemorrhage and death1. Despite decades of study, the entry receptors for YFV remain unclear. Here, using a surface protein-targeted CRISPR–Cas9 screen, we identified LRP4, a low-density lipoprotein receptor (LDLR) family member, as a candidate entry receptor for YFV. Genetic ablation of LRP4 impaired YFV infection of cells and, reciprocally, complementation or ectopic expression of LRP4 increased infection. Related viruses in the YFV antigenic complex also showed LRP4-dependent infection. LRP4 promoted YFV entry into cells through LDLR type A (LA) domain binding to domain III of the YFV envelope protein. Soluble LRP4–Fc decoy receptors neutralized YFV infection in cell culture and reduced viral burden in vivo. As we observed residual YFV infection in LRP4-deficient cells, we evaluated whether other LDLR family members promote YFV entry. This approach identified LRP1 and VLDLR as additional receptors for YFV infection in cell culture. LRP1–Fc, LRP4–Fc and VLDLR–Fc decoys protected mice from YFV challenge, and LRP1–Fc decoys inhibited YFV infection and liver pathogenesis in mice engrafted with human hepatocytes. A genetic deficiency of LRP1 in primary human hepatocyte cultures also resulted in reduced YFV infection. Our findings establish a role for multiple LDLR family members in YFV entry, infection and pathogenesis, which has implications for receptor use and countermeasure development for multiple emerging orthoflaviviruses.

DOI: 10.1038/s41586-025-09689-2

Source: https://www.nature.com/articles/s41586-025-09689-2