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LRP4 is an entry receptor for multiple encephalitic alphaviruses
Sicheng Tian (Shanghai Medical College of Fudan University, Fudan University), Bingting Ma (Tsinghua University), Hongyuan Guo (Shanghai Medical College of Fudan University, Fudan University), Zhenlu Chong (Washington University in St. Louis), Theron C. Gilliland (University of Pittsburgh), Sean Hui (Washington University in St. Louis), Guojie Wang (Shanghai Medical College of Fudan University, Fudan University), Yu-Yi Zhang (Shanghai Medical College of Fudan University, Fudan University), Jiayue Zhou (Shanghai Medical College of Fudan University, Fudan University), Alan Sariol (Washington University in St. Louis), Xinran Sun (Shanghai Medical College of Fudan University, Fudan University), Yingxin Hu (Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry), Zhuohao He (Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry), Daved H. Fremont (Washington University in St. Louis), William B. Klimstra (University of Pittsburgh), Michael Diamond (Washington University in St. Louis), Ye Xiang (Tsinghua University), Rong Zhang (Shanghai Medical College of Fudan University, Fudan University)
Résumé : 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. In this study, the authors identify LRP4 as an entry receptor for Eastern equine encephalitis virus, and show that decoy proteins block infection in neuronal cells, mice, and brain organoids, and that it is conserved across birds and mammals indicating a potential role in host range and transmission.