The VLDLR entry receptor is required for the pathogenesis of multiple encephalitic alphaviruses
The very-low-density lipoprotein receptor (VLDLR) has been reported as an entry receptor for Semliki Forest (SFV) and Eastern equine encephalitis (EEEV) alphaviruses in cell cultures. However, the role of VLDLR in alphavirus pathogenesis and the extent to which other alphaviruses can engage VLDLR remains unclear. Here, using a surface protein-targeted CRISPR-Cas9 screen, we identify VLDLR as a receptor for Western equine encephalitis virus (WEEV) and demonstrate that it promotes the infection of multiple viruses in the WEE antigenic complex. In vivo studies show that the pathogenicity of WEEV, EEEV, and SFV, but not the distantly related Venezuelan equine encephalitis virus, is markedly diminished in VLDLR-deficient mice and that mice treated with a soluble VLDLR-Fc decoy molecule are protected against disease. Overall, these results expand our understanding of the role of VLDLR in alphavirus pathogenesis and provide a potential path for developing countermeasures against alphaviruses from different antigenic complexes.
Authors
- Hongming Ma (ORCID: https://orcid.org/0000-0001-5105-1332)
- Zhuoming Liu (ORCID: https://orcid.org/0000-0001-8198-0976)
- Camille Carmona (ORCID: https://orcid.org/0000-0001-7725-391X)
- Sathvik Palakurty (ORCID: https://orcid.org/0000-0002-2222-4553)
- Ofer Zimmerman (ORCID: https://orcid.org/0000-0002-1684-4684)
- Daved H. Fremont (ORCID: https://orcid.org/0000-0002-8544-2689)
- Alan Sariol (ORCID: https://orcid.org/0000-0002-3127-0543)
- Zhenlu Chong (ORCID: https://orcid.org/0000-0001-6195-3452)
- Sean P. J. Whelan (ORCID: https://orcid.org/0000-0003-1564-8590)
- Lucas J. Adams (ORCID: https://orcid.org/0000-0002-1724-8120)
- William B. Klimstra
- Saravanan Raju (ORCID: https://orcid.org/0000-0003-3216-5574)
- Michael S. Diamond (ORCID: https://orcid.org/0000-0002-6646-6781)
- Ngan Wagoner
Institutions
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114809
- Citations
- 19
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 10.32
Funders
- Mallinckrodt Pharmaceuticals
- Moderna
- National Institutes of Health
- Defense Threat Reduction Agency
- National Institute of Allergy and Infectious Diseases
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases