Abstract
Encephalitic alphaviruses, including Eastern equine encephalitis virus (EEEV), cause severe neurological disease with high mortality rates, and thus are a public health threat. Although members of the low-density lipoprotein receptor (LDLR) family, including VLDLR, LRP8 (ApoER2), and LDLR recently were identified as receptors for EEEV, residual infection in receptor-deficient cells suggests that additional entry factors exist. Using a CRISPR-based activation screen, we identified LDLR-related protein 4 (LRP4) as a candidate entry factor for EEEV and several related alphaviruses (Western equine encephalitis, Semliki Forest, and Sindbis viruses). LRP4 mediates viral attachment and internalization, and its ligand-binding domain binds directly to virions. Soluble LRP4 decoy proteins potently inhibit EEEV infection in primary mouse neuronal cells, male mice, and human brain organoids, suggesting possible therapeutic applications. Mammalian and avian LRP4 orthologs demonstrate conserved functions in promoting EEEV infection, supporting a possible role in its host range of infection and transmission. Our findings establish LRP4 as a shared entry receptor for multiple alphaviruses and expand our understanding of alphavirus tropism, pathogenesis, and countermeasure development.
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Acknowledgements
We acknowledge Xiaoqing Sun at Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences of Fudan University and Hongbing Jiang at School of Public Health (Shenzhen), Sun Yat-sen University, for the help with next-generation sequencing, data analysis and validation. Figures 3A, D, F, H, 4J, and Supplementary Figs. 1D, 5C are generated using BioRender and are licensed under CC BY 4.0. Grants from the Shenzhen Medical Research Fund (B2302029 to R.Z.), Shanghai Municipal Science and Technology Major Project (ZD2021CY001 to R.Z.), Program of Shanghai Academic Research Leader (22XD1420600 to R.Z.), National Natural Science Foundation of China (81974305 to R.Z.), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2023-PT310-02 to R.Z.), and National Institutes of Health (R01AI143673 and R01AI164653 to M.S.D.) supported this work. Effort was sponsored by the U.S. Government (Defense Threat Reduction Agency) under contracts W15QKN-16-9-1002 and MCDC2103-01 (to W.B.K.) between the Medical CBRN Defense Consortium and the Government.
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M.S.D. is a consultant or on a Scientific Advisory Board for Inbios, IntegerBio, Akagera Medicines, GlaxoSmithKline, Merck, and Moderna. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna. The remaining authors declare no competing interests.
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Tian, S., Ma, B., Guo, H. et al. LRP4 is an entry receptor for multiple encephalitic alphaviruses. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73852-0
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DOI: https://doi.org/10.1038/s41467-026-73852-0
