期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：33
DOI：10.1073/pnas.2204706119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Emerging zoonotic viruses are at the forefront due to the ongoing COVID-19 pandemic. Bunyaviruses are a large group of diverse, arthropod-borne viruses that present concern due to reassortment and evolutionary capacity of their segmented RNA genomes. Here, we demonstrate that the conserved host cell surface receptor low-density lipoprotein receptor-related protein (Lrp1) facilitates efficient cellular infection by the South American bunyavirus Oropouche virus (OROV). Therefore, Lrp1 is a host factor for multiple bunyaviruses, including OROV and Rift Valley fever virus (RVFV), and it plays a broader role in bunyavirus infection than has been previously known. This is the first study to identify a pan-bunyaviral host factor with significant implications for therapeutic targets.
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.
