LDLR is used as a cell entry receptor by multiple alphaviruses

Xiaofeng Zhai, Xiaoling Li, Michael Veit, Ningning Wang, Yu Wang, Andres Merits, Zhiwen Jiang, Yan Qin, Xiaoguang Zhang, Kaili Qi, Houqi Jiao, Wan-Ting He, Ye Chen, Yang Mao () and Shuo Su ()
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Xiaofeng Zhai: Nanjing Agricultural University
Xiaoling Li: Nanjing Agricultural University
Michael Veit: Free University Berlin
Ningning Wang: Nanjing Agricultural University
Yu Wang: Nanjing Agricultural University
Andres Merits: University of Tartu
Zhiwen Jiang: Nanjing Agricultural University
Yan Qin: Nanjing Agricultural University
Xiaoguang Zhang: Nanjing Agricultural University
Kaili Qi: Nanjing Agricultural University
Houqi Jiao: Nanjing Agricultural University
Wan-Ting He: Nanjing Agricultural University
Ye Chen: Fujian Agriculture and Forestry University
Yang Mao: Sun Yat-sen University
Shuo Su: Nanjing Agricultural University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44872-5

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