@article{37b05502d19c47a088caaec7b6f6cea2,
title = "Lrp1 is a host entry factor for Rift Valley fever virus",
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.",
keywords = "CRISPR screen, Lrp1, Rift Valley fever virus, viral entry",
author = "Ganaie, {Safder S.} and Schwarz, {Madeline M.} and McMillen, {Cynthia M.} and Price, {David A.} and Feng, {Annie X.} and Albe, {Joseph R.} and Wenjie Wang and Shane Miersch and Anthony Orvedahl and Cole, {Aidan R.} and Sentmanat, {Monica F.} and Nawneet Mishra and Boyles, {Devin A.} and Koenig, {Zachary T.} and Kujawa, {Michael R.} and Demers, {Matthew A.} and Hoehl, {Ryan M.} and Moyle, {Austin B.} and Wagner, {Nicole D.} and Stubbs, {Sarah H.} and Lia Cardarelli and Joan Teyra and Anita McElroy and Gross, {Michael L.} and Whelan, {Sean P.J.} and John Doench and Xiaoxia Cui and Brett, {Tom J.} and Sidhu, {Sachdev S.} and Virgin, {Herbert W.} and Takeshi Egawa and Leung, {Daisy W.} and Amarasinghe, {Gaya K.} and Hartman, {Amy L.}",
note = "Funding Information: We thank members of our groups for discussions and support. We also thank Drs. J. Boon, M. Diamond, and S. Khader for providing critical reagents and for discussion. We thank Dr. A. Schwartz (Washington University School of Medicine) and J. Herz (UT Southwestern) for critical discussions and for their encouragement to embark on studies on Lrp1. We also thank R. Ridings and S. Barrick for coordinating studies between WUSM and Pitt, and E.O.L. Amarasinghe and E.E.L. Amarasinghe for assistance with Figure 1. We thank the Microscopy Resources on the North Quad (MicRoN) core at Harvard Medical School for imaging and image analysis assistance. We thank Bruker for technical and instrument support, and PMI who donated the software used for deconvolution (R42GM1213302 supported the software). We also thank the Genome Engineering and iPSC Center (GEiC) at the Washington University in St. Louis for gRNA validation services. Research was supported by NIH (R01AI161765 and R21AI163603 to G.K.A and A.L.H.; R01NS101100 to A.L.H.; P01AI120943 and R01AI123926 to G.K.A.; R01AI107056 to D.W.L.; U19AI142784 and U19AI10972505 to H.W.V.; R01AI130152 to T.E.; T32AI060525 to C.M.M.; T32AI106688 and 1K08AI144033 to A.O.; R37 AI059371 to S.P.J.W.; R24GM136766 and P41GM103422 to M.L.G.). A.K.M was supported by a Burroughs Wellcome CAMS award (1013362.02). Additional support was provided by the Pediatric Infectious Diseases Society, St. Jude Children's Research Hospital Fellowship Program in Basic Research, and Society for Pediatric Research Physician Scientist Bridging to Success Award to A.O.; Alzheimer's Association (AARG-16-441560 to T.J.B); and The Leukemia and Lymphoma Society Scholar Award to T.E. G.K.A. and A.L.H. conceived the overall project. All authors designed, performed, and analyzed results. S.S.G. D.W.L. G.K.A. and A.L.H. wrote the manuscript with input from all the authors. H.W.V. is a founder of Casma Therapeutics and pierianDx and is employed by Vir Biotechnology. None of these companies funded the work reported here. Invention disclosures for method of use for Lrp1 interaction with RVFV Gn (G.K.A. A.L.H. D.W.L. H.W.V. and S.S.G.) and for the use of anti-Lrp1 antibodies by U Toronto (S.S.S. S.M. and G.K.A.) have been filed. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We thank members of our groups for discussions and support. We also thank Drs. J. Boon, M. Diamond, and S. Khader for providing critical reagents and for discussion. We thank Dr. A. Schwartz (Washington University School of Medicine) and J. Herz (UT Southwestern) for critical discussions and for their encouragement to embark on studies on Lrp1. We also thank R. Ridings and S. Barrick for coordinating studies between WUSM and Pitt, and E.O.L. Amarasinghe and E.E.L. Amarasinghe for assistance with Figure 1 . We thank the Microscopy Resources on the North Quad (MicRoN) core at Harvard Medical School for imaging and image analysis assistance. We thank Bruker for technical and instrument support, and PMI who donated the software used for deconvolution (R42GM1213302 supported the software). We also thank the Genome Engineering and iPSC Center (GEiC) at the Washington University in St. Louis for gRNA validation services. Research was supported by NIH ( R01AI161765 and R21AI163603 to G.K.A and A.L.H.; R01NS101100 to A.L.H.; P01AI120943 and R01AI123926 to G.K.A.; R01AI107056 to D.W.L.; U19AI142784 and U19AI10972505 to H.W.V.; R01AI130152 to T.E.; T32AI060525 to C.M.M.; T32AI106688 and 1K08AI144033 to A.O.; R37 AI059371 to S.P.J.W.; R24GM136766 and P41GM103422 to M.L.G.). A.K.M was supported by a Burroughs Wellcome CAMS award ( 1013362.02 ). Additional support was provided by the Pediatric Infectious Diseases Society , St. Jude Children{\textquoteright}s Research Hospital Fellowship Program in Basic Research , and Society for Pediatric Research Physician Scientist Bridging to Success Award to A.O.; Alzheimer's Association ( AARG-16-441560 to T.J.B); and The Leukemia and Lymphoma Society Scholar Award to T.E. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = sep,
day = "30",
doi = "10.1016/j.cell.2021.09.001",
language = "English",
volume = "184",
pages = "5163--5178.e24",
journal = "Cell",
issn = "0092-8674",
number = "20",
}