@article{8878760696f847a0aa02f9b3d1b169e1,
title = "Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1",
abstract = "Oropouche orthobunyavirus (OROV; Peribunyaviridae) is a mosquito-transmitted virus that causes widespread human febrile illness in South America, with occasional progression to neurologic effects. Host factors mediating the cellular entry of OROV are undefined. Here, we show that OROV uses the host protein low-density lipoprotein–related protein 1 (Lrp1) for efficient cellular infection. Cells from evolutionarily distinct species lacking Lrp1 were less permissive to OROV infection than cells with Lrp1. Treatment of cells with either the high-affinity Lrp1 ligand receptor-associated protein (RAP) or recombinant ectodomain truncations of Lrp1 significantly reduced OROV infection. In addition, chimeric vesicular stomatitis virus (VSV) expressing OROV glycoproteins (VSV-OROV) bound to the Lrp1 ectodomain in vitro. Furthermore, we demonstrate the biological relevance of the OROV-Lrp1 interaction in a proof-of-concept mouse study in which treatment of mice with RAP at the time of infection reduced tissue viral load and promoted survival from an otherwise lethal infection. These results with OROV, along with the recent finding of Lrp1 as an entry factor for Rift Valley fever virus, highlight the broader significance of Lrp1 in cellular infection by diverse bunyaviruses. Shared strategies for entry, such as the critical function of Lrp1 defined here, provide a foundation for the development of pan-bunyaviral therapeutics.",
keywords = "Lrp1, Oropouche virus, bunyavirus, entry factor, lipoprotein",
author = "Schwarz, {Madeline M.} and Price, {David A.} and Ganaie, {Safder S.} and Annie Feng and Nawneet Mishra and Hoehl, {Ryan M.} and Farheen Fatma and Stubbs, {Sarah H.} and Whelan, {Sean P.J.} and Xiaoxia Cui and Takeshi Egawa and Leung, {Daisy W.} and Amarasinghe, {Gaya K.} and Hartman, {Amy L.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank members of our research groups for helpful discussions and support. We thank W. Paul Duprex and Natasha Tilston-Lunel (University of Pittsburgh) for providing the OROV virus used in these studies. The authors also thank Stacey Barrick for coordinating housing for the animal studies. The following reagents were obtained through BEI Resources, National Institute of Allergy and Infectious Diseases, NIH: Zika virus, PRVABC59, NR-50240; RVFV anti-N mAb, Clone 1D8, NR-43188. Research was supported by NIH grants (R01AI161765 and R21AI163603, to G.K.A. and A.L.H.; R01NS101100, to A.L.H.; P01AI120943, to G.K.A.; R01AI140758, to D.W.L.; and R01AI130152, to T.E.). D.A.P. was supported by R01AI40758-S1. Funding Information: We thank members of our research groups for helpful discussions and support. We thank W. Paul Duprex and Natasha Tilston-Lunel (University of Pittsburgh) for providing the OROV virus used in these studies. The authors also thank Stacey Barrick for coordinating housing for the animal studies. The following reagents were obtained through BEI Resources, National Institute of Allergy and Infectious Diseases, NIH: Zika virus, PRVABC59, NR-50240; RVFV anti-N mAb, Clone 1D8, NR-43188. Research was supported by NIH grants (R01AI161765 and R21AI163603, to G.K.A. and A.L.H.; R01NS101100, to A.L.H.; P01AI120943, to G.K.A.; R01AI140758, to D.W.L.; and R01AI130152, to T.E.). D.A.P. was supported by R01AI40758-S1. Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s).",
year = "2022",
month = aug,
day = "16",
doi = "10.1073/pnas.2204706119",
language = "English",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "33",
}