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Updated: Oct 19, 2025
Using Reverse Genetics to Manipulate the NSs Gene of the Rift Valley Fever Virus MP-12 Strain to Improve Vaccine Safety and Efficacy
Published on: November 1, 2011
Lrp1 is a host entry factor for Rift Valley fever virus
Safder S Ganaie1, Madeline M Schwarz2, Cynthia M McMillen2
1Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Abstract:
Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor-associated protein (RAP) as critical host factors for RVFV infection. RVFV Gn directly binds to specific Lrp1 clusters and is glycosylation independent. Exogenous addition of murine RAP domain 3 (mRAPD3) and anti-Lrp1 antibodies neutralizes RVFV infection in taxonomically diverse cell lines. Mice treated with mRAPD3 and infected with pathogenic RVFV are protected from disease and death. A mutant mRAPD3 that binds Lrp1 weakly failed to protect from RVFV infection. Together, these data support Lrp1 as a host entry factor for RVFV infection and define a new target to limit RVFV infections.
Insights
Rift Valley fever virus (RVFV) uses low-density lipoprotein receptor-related protein 1 (Lrp1) to enter cells. Targeting Lrp1 with therapies like murine RAP domain 3 (mRAPD3) can block RVFV infection and protect mice.
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.
