The VLDLR entry receptor is required for the pathogenesis of multiple encephalitic alphaviruses
Sathvik Palakurty,
Saravanan Raju,
Alan Sariol,
Zhenlu Chong,
Ngan Wagoner,
Hongming Ma,
Ofer Zimmerman,
Lucas J. Adams,
Camille Carmona,
Zhuoming Liu,
Daved H. Fremont,
Sean P.J. Whelan,
William B. Klimstra,
Michael S. Diamond
Affiliations
Sathvik Palakurty
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Saravanan Raju
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Alan Sariol
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Zhenlu Chong
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Ngan Wagoner
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Hongming Ma
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Ofer Zimmerman
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Lucas J. Adams
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Camille Carmona
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Zhuoming Liu
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Daved H. Fremont
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
Sean P.J. Whelan
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
William B. Klimstra
The Center for Vaccine Research and Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15261, USA
Michael S. Diamond
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, Saint Louis, MO 63110, USA; Corresponding author
Summary: 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.
