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LRP4 is an entry receptor for multiple encephalitic alphaviruses
Sicheng Tian1, Bingting Ma2, Hongyuan Guo1
1Key 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.
Nature Communications
|June 9, 2026
Summary
Low-density lipoprotein receptor-related protein 4 (LRP4) is a newly discovered shared entry receptor for Eastern equine encephalitis virus (EEEV) and other alphaviruses. This finding offers potential for developing new countermeasures against these dangerous neurotropic viruses.
Area of Science:
- Virology
- Neuroscience
- Infectious Diseases
Background:
- Encephalitic alphaviruses, such as Eastern equine encephalitis virus (EEEV), pose a significant public health risk due to severe neurological disease and high mortality.
- While LDLR family members (VLDLR, LRP8, LDLR) are known EEEV receptors, incomplete infection in deficient cells indicates other factors are involved.
Purpose of the Study:
- To identify novel cellular entry factors for EEEV and related alphaviruses.
- To investigate the role of identified factors in viral entry and pathogenesis.
- To explore potential therapeutic strategies targeting these entry factors.
Main Methods:
- CRISPR-based activation screen to identify host factors.
- Viral attachment and internalization assays.
- Binding assays using soluble decoy proteins.
- Infection studies in cell cultures, animal models, and organoids.
Main Results:
- Low-density lipoprotein receptor-related protein 4 (LRP4) was identified as a novel entry factor for EEEV and other alphaviruses.
- LRP4 mediates alphavirus attachment and internalization, with direct binding to virions.
- Soluble LRP4 decoy proteins demonstrated potent inhibition of EEEV infection in various models.
- Conserved function of LRP4 orthologs across species suggests a role in host range and transmission.
Conclusions:
- LRP4 serves as a shared entry receptor for multiple alphaviruses, including EEEV.
- Understanding LRP4's role expands knowledge of alphavirus tropism and pathogenesis.
- LRP4 presents a promising target for developing novel therapeutic countermeasures against alphavirus infections.
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