Mittler Eva, Tse Alexandra L, Tran Pham-Tue-Hung, Florez Catalina, Janer Javier, Varnaite Renata, Kasikci Ezgi, Mv Vasantha Kumar, Loomis Michaela, Christ Wanda, Cazares Erik, Bakken Russell R, Martin Caroline K, Zeng Xiankun, Raymond Jo Lynne, Shahsavani Mansoureh, Khanal Sara, Wilkinson Eric R, Oktavia Rischa Maya, Slough Megan M, Haslwanter Denise, Han Julianna, Berrigan Jacob, Rosendal Ebba, Kielian Margaret, Manicassamy Balaji, Överby Anna K, Falk Anna, Barba-Spaeth Giovanna, Rey Felix A, Klingström Jonas, Gavathiotis Evripidis, Herbert Andrew S, Chandran Kartik, Gredmark-Russ Sara
Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA.
Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.
Nature. 2025 Oct;646(8086):945-952. doi: 10.1038/s41586-025-09500-2. Epub 2025 Sep 24.
Tick-borne encephalitis virus (TBEV) causes tick-borne encephalitis (TBE), a severe and sometimes life-threatening disease characterized by viral invasion of the central nervous system with symptoms of neuroinflammation. As with other orthoflaviviruses-enveloped, arthropod-borne RNA viruses-host factors required for TBEV entry remain poorly defined. Here we used a genome-scale CRISPR-Cas9-based screen to identify LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, as a TBEV receptor. LRP8 downregulation reduced TBEV infection in human cells, and its overexpression enhanced infection. LRP8 bound directly to the TBEV E glycoprotein and mediated viral attachment and internalization into cells. An LRP8-based soluble decoy blocked infection of human cell lines and neuronal cells and protected mice from lethal TBEV challenge. LRP8's role as a TBEV receptor has implications for TBEV neuropathogenesis and the development of antiviral countermeasures.
蜱传脑炎病毒（TBEV）可引发蜱传脑炎（TBE），这是一种严重的、有时甚至会危及生命的疾病，其特征是病毒侵袭中枢神经系统并伴有神经炎症症状。与其他正黄病毒（包膜虫媒RNA病毒）一样，TBEV进入宿主细胞所需的宿主因子仍不清楚。在此，我们利用基于基因组规模CRISPR-Cas9的筛选方法，鉴定出低密度脂蛋白受体相关蛋白8（LRP8）——一种在大脑中高表达的载脂蛋白E和reelin受体——作为TBEV受体。LRP8表达下调可减少人细胞中的TBEV感染，而其过表达则会增强感染。LRP8直接与TBEV E糖蛋白结合，并介导病毒附着及内化进入细胞。基于LRP8的可溶性诱饵可阻断人细胞系和神经元细胞的感染，并保护小鼠免受致死性TBEV攻击。LRP8作为TBEV受体的作用对TBEV神经病理学及抗病毒对策的开发具有重要意义。
