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

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 journal › Article › peer-review

49 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 (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.

Original language	English
Pages (from-to)	5163-5178.e24
Journal	Cell
Volume	184
Issue number	20
DOIs	https://doi.org/10.1016/j.cell.2021.09.001
State	Published - Sep 30 2021

Keywords

CRISPR screen
Lrp1
Rift Valley fever virus
viral entry

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10.1016/j.cell.2021.09.001

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Ganaie, S. S., Schwarz, M. M., McMillen, C. M., Price, D. A., Feng, A. X., Albe, J. R., Wang, W., Miersch, S., Orvedahl, A., Cole, A. R., Sentmanat, M. F., Mishra, N., Boyles, D. A., Koenig, Z. T., Kujawa, M. R., Demers, M. A., Hoehl, R. M., Moyle, A. B., Wagner, N. D., ... Hartman, A. L. (2021). Lrp1 is a host entry factor for Rift Valley fever virus. Cell, 184(20), 5163-5178.e24. https://doi.org/10.1016/j.cell.2021.09.001

@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 = "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",

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Ganaie, SS, Schwarz, MM, McMillen, CM, Price, DA, Feng, AX, Albe, JR, Wang, W, Miersch, S, Orvedahl, A, Cole, AR, Sentmanat, MF, Mishra, N, Boyles, DA, Koenig, ZT, Kujawa, MR, Demers, MA, Hoehl, RM, Moyle, AB, Wagner, ND, Stubbs, SH, Cardarelli, L, Teyra, J, McElroy, A, Gross, ML , Whelan, SPJ, Doench, J, Cui, X , Brett, TJ, Sidhu, SS, Virgin, HW, Egawa, T , Leung, DW , Amarasinghe, GK & Hartman, AL 2021, 'Lrp1 is a host entry factor for Rift Valley fever virus', Cell, vol. 184, no. 20, pp. 5163-5178.e24. https://doi.org/10.1016/j.cell.2021.09.001

TY - JOUR

T1 - Lrp1 is a host entry factor for Rift Valley fever virus

AU - Ganaie, Safder S.

AU - Schwarz, Madeline M.

AU - McMillen, Cynthia M.

AU - Price, David A.

AU - Feng, Annie X.

AU - Albe, Joseph R.

AU - Wang, Wenjie

AU - Miersch, Shane

AU - Orvedahl, Anthony

AU - Cole, Aidan R.

AU - Sentmanat, Monica F.

AU - Mishra, Nawneet

AU - Boyles, Devin A.

AU - Koenig, Zachary T.

AU - Kujawa, Michael R.

AU - Demers, Matthew A.

AU - Hoehl, Ryan M.

AU - Moyle, Austin B.

AU - Wagner, Nicole D.

AU - Stubbs, Sarah H.

AU - Cardarelli, Lia

AU - Teyra, Joan

AU - McElroy, Anita

AU - Gross, Michael L.

AU - Whelan, Sean P.J.

AU - Doench, John

AU - Cui, Xiaoxia

AU - Brett, Tom J.

AU - Sidhu, Sachdev S.

AU - Virgin, Herbert W.

AU - Egawa, Takeshi

AU - Leung, Daisy W.

AU - Amarasinghe, Gaya K.

AU - Hartman, Amy L.

PY - 2021/9/30

Y1 - 2021/9/30

N2 - 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.

AB - 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.

KW - CRISPR screen

KW - Lrp1

KW - Rift Valley fever virus

KW - viral entry

UR - http://www.scopus.com/inward/record.url?scp=85116035606&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.09.001

DO - 10.1016/j.cell.2021.09.001

M3 - Article

C2 - 34559985

AN - SCOPUS:85116035606

SN - 0092-8674

VL - 184

SP - 5163-5178.e24

JO - Cell

JF - Cell

IS - 20

ER -

Lrp1 is a host entry factor for Rift Valley fever virus

Abstract

Keywords

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