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

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• The very-low-density lipoprotein receptor (VLDLR) is a known entry receptor for certain alphaviruses like Semliki Forest virus (SFV) and Eastern equine encephalitis virus (EEEV) in cell cultures.
• The broader role of VLDLR in alphavirus pathogenesis and its interaction with other alphaviruses, particularly within different antigenic complexes, remains largely unexplored.

Purpose of the Study:

• To identify novel alphavirus receptors using a genome-wide CRISPR-Cas9 screen.
• To investigate the role of VLDLR in the pathogenesis of Western equine encephalitis virus (WEEV) and other related alphaviruses.
• To evaluate the therapeutic potential of targeting VLDLR against alphavirus infections.

Main Methods:

• A surface protein-targeted CRISPR-Cas9 screen was employed to identify host cell entry factors for alphaviruses.
• In vitro infection assays were performed using VLDLR-deficient cells and wild-type cells.
• In vivo studies utilized VLDLR-deficient mice and soluble VLDLR-Fc decoy molecules to assess protection against alphavirus challenge.

Main Results:

• VLDLR was identified as a critical entry receptor for WEEV and other viruses within the WEE antigenic complex.
• Pathogenicity of WEEV, EEEV, and SFV was significantly reduced in VLDLR-deficient mice.
• Treatment with a soluble VLDLR-Fc decoy molecule conferred protection against alphavirus-induced disease in mice.

Conclusions:

• VLDLR plays a significant role in the pathogenesis of multiple alphaviruses, including those from different antigenic complexes.
• Targeting VLDLR presents a promising strategy for developing broad-spectrum countermeasures against alphavirus infections.