LDLR is used as a cell entry receptor by multiple alphaviruses

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Alphaviruses are mosquito-borne arboviruses posing significant public health risks to humans and livestock.
• Existing identified receptors do not fully explain the broad host range and tissue tropism observed in some alphaviruses, like Getah virus (GETV).

Purpose of the Study:

• To identify novel cellular receptors involved in alphavirus entry.
• To investigate the role of the low-density lipoprotein receptor (LDLR) in the cellular entry of GETV and other alphaviruses.

Main Methods:

• Ectopic expression of LDLR in cells.
• Analysis of GETV binding and internalization mediated by LDLR.
• Investigating the interaction between viral E2-E1 spike and LDLR ligand-binding domain (LBD).
• Utilizing antibodies against LBD and GST-LBD fusion proteins to inhibit viral infection.
• Site-directed mutagenesis of key amino acids in LDLR-LBD.

Main Results:

• The low-density lipoprotein receptor (LDLR) was identified as a novel cell entry factor for GETV, Semliki Forest virus (SFV), Ross River virus (RRV), and Bebaru virus (BEBV).
• LDLR facilitates GETV cellular binding and internalization through interaction between the viral E2-E1 spike and the LDLR ligand-binding domain (LBD).
• Antibodies against LBD and a GST-LBD fusion protein effectively inhibited GETV infection in vitro and in vivo.
• Specific mutations within the CR4 and CR5 domains of LDLR-LBD significantly reduced viral entry by over 20-fold.

Conclusions:

• The low-density lipoprotein receptor (LDLR) is a conserved cell entry factor for multiple alphaviruses.
• The interaction between the alphavirus E2-E1 spike and the LDLR-LBD is critical for viral entry.
• Targeting the LDLR-LBD presents a promising therapeutic strategy for developing antivirals against a range of alphaviruses.