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.

中文翻译：

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Oropouche 正布尼亚病毒感染由细胞宿主因子 Lrp1 介导


奥罗普切正布尼亚病毒（OROV；近布尼亚病毒科）是一种通过蚊子传播的病毒，在南美洲引起广泛的人类发热性疾病，偶尔会发展为神经系统影响。介导 OROV 进入细胞的宿主因素尚不清楚。在这里，我们证明 OROV 使用宿主蛋白低密度脂蛋白相关蛋白 1 (Lrp1) 进行有效的细胞感染。来自进化上不同物种、缺乏 Lrp1 的细胞比具有 Lrp1 的细胞更不容易感染 OROV。用高亲和力 Lrp1 配体受体相关蛋白 (RAP) 或 Lrp1 重组胞外域截断物处理细胞可显着减少 OROV 感染。此外，表达 OROV 糖蛋白 (VSV-OROV) 的嵌合水泡性口炎病毒 (VSV) 在体外与 Lrp1 胞外域结合。此外，我们在一项概念验证小鼠研究中证明了 OROV-Lrp1 相互作用的生物学相关性，其中在感染时用 RAP 治疗小鼠可减少组织病毒载量并促进其他致命感染的存活。 OROV 的这些结果，以及最近发现的 Lrp1 作为裂谷热病毒的进入因子，突显了 Lrp1 在不同布尼亚病毒的细胞感染中的更广泛意义。共享的进入策略，例如此处定义的 Lrp1 的关键功能，为泛布尼亚病毒疗法的发展奠定了基础。