The VLDLR entry receptor is required for the pathogenesis of multiple encephalitic alphaviruses

• Published in: Cell reports (Cambridge) Vol. 43; no. 10; p. 114809
• Main Authors: Palakurty, Sathvik, Raju, Saravanan, Sariol, Alan, Chong, Zhenlu, Wagoner, Ngan, Ma, Hongming, Zimmerman, Ofer, Adams, Lucas J., Carmona, Camille, Liu, Zhuoming, Fremont, Daved H., Whelan, Sean P.J., Klimstra, William B., Diamond, Michael S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.10.2024; Elsevier
• Subjects: alphavirus; Alphavirus - pathogenicity; Alphavirus Infections - pathology; Alphavirus Infections - virology; Animals; CP: Immunology; CP: Microbiology; decoy; Encephalitis Virus, Western Equine - metabolism; Encephalitis Virus, Western Equine - pathogenicity; HEK293 Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; pathogenesis; Receptor; Receptors, LDL - genetics; Receptors, LDL - metabolism; therapy; tropism; Virus Internalization; CP: Immunology; pathogenesis; Receptor; therapy; CP: Microbiology; tropism; alphavirus; decoy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114809

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. [Display omitted] •VLDLR is a receptor for several WEEV strains•Soluble VLDLR decoy neutralizes WEEV infection in vitro and in vivo•VLDLR KO mice survive lethal challenge by WEEV, SFV, and EEEV-MADV but not VEEV•VLDLR KO mice have decreased virus in the brain after intracranial WEEV infection Using a targeted CRISPR-Cas9 survival screen, Palakurty et al. identify the very-low-density lipoprotein receptor (VLDLR) as a receptor for Western equine encephalitis virus (WEEV) and other related viruses in its antigenic complex. Their experiments also demonstrate that the pathogenesis of multiple encephalitic alphaviruses is substantially reduced in VLDLR-deficient mice.