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. StubbsLia 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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Pages (from-to)5163-5178.e24
JournalCell
Volume184
Issue number20
DOIs
StatePublished - Sep 30 2021

Keywords

  • CRISPR screen
  • Lrp1
  • Rift Valley fever virus
  • viral entry

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