Lrp1 is a host entry factor for Rift Valley fever virus

Area of Science:

• Virology
• Infectious Diseases
• Molecular Biology

Background:

• Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential.
• RVFV entry mechanisms are not fully understood, with the viral glycoprotein (Gn) mediating cell entry.
• Host factors facilitating RVFV infection are largely undefined.

Purpose of the Study:

• To identify host factors critical for RVFV entry.
• To investigate the role of identified factors in RVFV infection.
• To explore potential therapeutic strategies targeting host entry factors.

Main Methods:

• Genome-wide CRISPR screen to identify host factors.
• Biochemical assays to confirm direct binding of RVFV Gn to Lrp1.
• In vitro neutralization assays using mRAPD3 and anti-Lrp1 antibodies.
• In vivo protection studies in mice treated with mRAPD3.

Main Results:

• A CRISPR screen identified Lrp1, Grp94, and RAP as essential host factors for RVFV infection.
• RVFV Gn directly binds to Lrp1 clusters independently of glycosylation.
• mRAPD3 and anti-Lrp1 antibodies effectively neutralized RVFV in diverse cell lines.
• Treatment with mRAPD3 conferred significant protection against pathogenic RVFV infection in mice.

Conclusions:

• Low-density lipoprotein receptor-related protein 1 (Lrp1) is a critical host entry factor for RVFV.
• RVFV Gn directly interacts with Lrp1 to facilitate viral entry.
• Targeting the Lrp1-RVFV interaction with agents like mRAPD3 offers a promising therapeutic strategy against RVFV.