Amarasinghe, Gaya K

Cui, Xiaoxia

Egawa, Takeshi

Fatma, Farheen

Feng, Annie

Ganaie, Safder S

Hartman, Amy L

Hoehl, Ryan M

Leung, Daisy W

Mishra, Nawneet

Price, David A

Schwarz, Madeline M

Stubbs, Sarah H

Whelan, Sean P J

Proceedings of the National Academy of Sciences

English

PubMed


            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.
          </jats:p

Madeline M. Schwarz

David A. Price

Safder S. Ganaie

Annie Feng

Nawneet Mishra

Ryan M. Hoehl

Farheen Fatma

Sarah H. Stubbs

Sean P. J. Whelan

Xiaoxia Cui

Takeshi Egawa

Daisy W. Leung

Gaya K. Amarasinghe

Amy L. Hartman

Crossref

Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1

Digital Commons@Becker

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

Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1

Abstract

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Digital Commons@Becker

PubMed Central