Lrp1 is a host entry factor for Rift Valley fever virus

Safder S Ganaie; Madeline M Schwarz; Cynthia M McMillen; David A Price; Annie X Feng; Joseph R Albe; Wenjie Wang; Shane Miersch; Anthony Orvedahl; Aidan R Cole; Monica F Sentmanat; Nawneet Mishra; Devin A Boyles; Zachary T Koenig; Michael R Kujawa; Matthew A Demers; Ryan M Hoehl; Austin B Moyle; Nicole D Wagner; Sarah H Stubbs; Lia Cardarelli; Joan Teyra; Anita McElroy; Michael L Gross; Sean P J Whelan; John Doench; Xiaoxia Cui; Tom J Brett; Sachdev S Sidhu; Herbert W Virgin; Takeshi Egawa; Daisy W Leung; Gaya K Amarasinghe; Amy L Hartman

doi:10.1016/j.cell.2021.09.001

Lrp1 is a host entry factor for Rift Valley fever virus

Cell. 2021 Sep 30;184(20):5163-5178.e24. doi: 10.1016/j.cell.2021.09.001. Epub 2021 Sep 23.

Authors

Safder S Ganaie¹, Madeline M Schwarz², Cynthia M McMillen², David A Price¹, Annie X Feng¹, Joseph R Albe³, Wenjie Wang¹, Shane Miersch⁴, Anthony Orvedahl⁵, Aidan R Cole¹, Monica F Sentmanat⁶, Nawneet Mishra¹, Devin A Boyles³, Zachary T Koenig², Michael R Kujawa², Matthew A Demers³, Ryan M Hoehl³, Austin B Moyle⁷, Nicole D Wagner⁷, Sarah H Stubbs⁸, Lia Cardarelli⁴, Joan Teyra⁴, Anita McElroy⁹, Michael L Gross⁷, Sean P J Whelan¹⁰, John Doench¹¹, Xiaoxia Cui⁶, Tom J Brett¹², Sachdev S Sidhu⁴, Herbert W Virgin¹³, Takeshi Egawa¹, Daisy W Leung¹⁴, Gaya K Amarasinghe¹⁵, Amy L Hartman¹⁶

Affiliations

¹ Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
² Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
³ Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
⁵ Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
⁶ Genome Engineering and iPSC Center (GEiC), Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
⁷ Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA.
⁸ Department of Microbiology, Harvard Medical School, Boston, MA, USA.
⁹ Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, Division of Pediatric Infectious Disease, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
¹³ Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; Current address: Vir Biotechnology, San Francisco, CA, USA.
¹⁴ Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
¹⁵ Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. Electronic address: gamarasinghe@wustl.edu.
¹⁶ Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: hartman2@pitt.edu.

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 (mRAP_D3) and anti-Lrp1 antibodies neutralizes RVFV infection in taxonomically diverse cell lines. Mice treated with mRAP_D3 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.

Keywords: CRISPR screen; Lrp1; Rift Valley fever virus; viral entry.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibody Specificity / immunology
Base Sequence
Brain / pathology
Brain / virology
CRISPR-Cas Systems / genetics
Cell Membrane / metabolism
Cells, Cultured
Glycoproteins / metabolism
Glycosaminoglycans / metabolism
Glycosylation
Host-Pathogen Interactions*
Humans
LDL-Receptor Related Protein-Associated Protein / metabolism
Ligands
Low Density Lipoprotein Receptor-Related Protein-1 / deficiency
Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
Membrane Glycoproteins / metabolism
Mice
Protein Binding
Protein Denaturation
Rift Valley Fever / pathology
Rift Valley Fever / prevention & control
Rift Valley Fever / virology
Rift Valley fever virus / immunology
Rift Valley fever virus / physiology*
Virus Internalization*

Substances

Glycoproteins
Glycosaminoglycans
LDL-Receptor Related Protein-Associated Protein
Ligands
Low Density Lipoprotein Receptor-Related Protein-1
Membrane Glycoproteins
endoplasmin

Abstract

Publication types

MeSH terms

Substances

Grants and funding