OmniVira

LRP4 is an entry receptor for multiple encephalitic alphaviruses.

Sicheng Tian1 Bingting Ma2 Hongyuan Guo1 Zhenlu Chong3 Theron C Gilliland4 Sean Hui3 Guojie Wang1 Yuyi Zhang1 Jiayue Zhou1 Alan Sariol3 Xinran Sun1 Yingxin Hu5 Zhuohao He5 Daved H Fremont3 William B Klimstra4 Michael S Diamond6 Ye Xiang7 Rong Zhang8
Affiliations 8 institutions
  1. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  2. Beijing Frontier Research Center for Biological Structure, Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China.
  3. Departments of Medicine, Pathology & Immunology, and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
  4. The Center for Vaccine Research and Department of Immunology, The University of Pittsburgh, Pittsburgh, PA, USA.
  5. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China.
  6. Departments of Medicine, Pathology & Immunology, and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  7. Beijing Frontier Research Center for Biological Structure, Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. [email protected].
  8. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
PMID42265108 DOI10.1038/s41467-026-73852-0 Year2026 Journal Nature communications Nat Commun Languageeng Statusaheadofprint

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.

Supporting text Virus Host Location

Evidence records

1 total
Experimental Infection
1 records · 1 evidence types
Evidence type Host Range Experiment
1 records
OVE11306 Host Range Experiment
Key finding

Mammalian and avian LRP4 orthologs were experimentally shown to support Eastern equine encephalitis virus entry and infection, indicating conserved susceptibility across these host groups.

Virus
Eastern equine encephalomyelitis virus
Host
birds Aves Experimental system
Location
Not specified
Supporting text

Mammalian and avian LRP4 orthologs demonstrate conserved functions in promoting EEEV infection, supporting a possible role in its host range of infection and transmission.

Method
receptor-expression assay | infectivity assay | cell-based viral entry test
Experimental system
receptor-expression and cell-based infection assay using mammalian and avian LRP4 orthologs