LDLR is used as a cell entry receptor by multiple alphaviruses

• Published in: Nature communications Vol. 15; no. 1; p. 622
• Main Authors: Zhai, Xiaofeng, Li, Xiaoling, Veit, Michael, Wang, Ningning, Wang, Yu, Merits, Andres, Jiang, Zhiwen, Qin, Yan, Zhang, Xiaoguang, Qi, Kaili, Jiao, Houqi, He, Wan-Ting, Chen, Ye, Mao, Yang, Su, Shuo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-01-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 42; 45; 631/326/596/1282; 631/326/596/2557; 82/80; Alphavirus - genetics; Alphavirus Infections - genetics; Amino acids; Animals; Antibodies; Antiviral agents; Aquatic insects; Binding; Culicidae; Density; Development strategies; Ectopic expression; Fusion protein; Host range; Humanities and Social Sciences; Humans; Internalization; Livestock; Low density lipoprotein receptors; Mosquitoes; multidisciplinary; Public health; Receptor density; Receptors; RNA viruses; Science; Science (multidisciplinary); Semliki forest virus - genetics; Semliki forest virus - metabolism; Tropism; Veterinary medicine; Virus Internalization; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-44872-5

Alphaviruses are arboviruses transmitted by mosquitoes and are pathogenic to humans and livestock, causing a substantial public health burden. So far, several receptors have been identified for alphavirus entry; however, they cannot explain the broad host range and tissue tropism of certain alphaviruses, such as Getah virus (GETV), indicating the existence of additional receptors. Here we identify the evolutionarily conserved low-density lipoprotein receptor (LDLR) as a new cell entry factor for GETV, Semliki Forest virus (SFV), Ross River virus (RRV) and Bebaru virus (BEBV). Ectopic expression of LDLR facilitates cellular binding and internalization of GETV, which is mediated by the interaction between the E2-E1 spike of GETV and the ligand-binding domain (LBD) of LDLR. Antibodies against LBD block GETV infection in cultured cells. In addition, the GST-LBD fusion protein inhibits GETV infection both in vitro and in vivo. Notably, we identify the key amino acids in LDLR-LBD that played a crucial role in viral entry; specific mutations in the CR4 and CR5 domain of LDLR-LBD reduce viral entry to cells by more than 20-fold. These findings suggest that targeting the LDLR-LBD could be a potential strategy for the development of antivirals against multiple alphaviruses.
Getah virus (GETV), is a mosquito-borne alphavirus of importance in veterinary medicine. Here, the authors show that evolutionarily conserved low-density lipoprotein receptor (LDLR) functions as a receptor for GETV, which may explain the multi-species spread of this virus.