Mammalian orthoreovirus (reovirus) is a nonenveloped virus that establishes primary infection in the intestine and disseminates to sites of secondary infection, including the CNS. Reovirus entry involves multiple engagement factors, but how the virus disseminates systemically and targets neurons remains unclear. In this study, we identified murine neuropilin 1 (mNRP1) as a receptor for reovirus. mNRP1 binds reovirus with nanomolar affinity using a unique mechanism of virus-receptor interaction, which is coordinated by multiple interactions between distinct reovirus capsid subunits and multiple NRP1 extracellular domains. By exchanging essential capsid protein-encoding gene segments, we determined that the multivalent interaction is mediated by outer-capsid protein σ3 and capsid turret protein λ2. Using capsid mutants incapable of binding NRP1, we found that NRP1 contributes to reovirus dissemination and neurovirulence in mice. Collectively, our results demonstrate that NRP1 is an entry receptor for reovirus and uncover mechanisms by which NRPs promote viral entry and pathogenesis.

哺乳动物正呼肠孤病毒（呼肠孤病毒）是一种无包膜病毒，可在肠道内引起原发感染，并传播至继发感染部位，包括中枢神经系统。呼肠孤病毒的进入涉及多种参与因素，但病毒如何全身传播并靶向神经元仍不清楚。在这项研究中，我们确定了鼠神经毡蛋白 1 (mNRP1) 是呼肠孤病毒的受体。 mNRP1 使用独特的病毒-受体相互作用机制以纳摩尔亲和力结合呼肠孤病毒，该机制通过不同呼肠孤病毒衣壳亚基和多个 NRP1 胞外域之间的多重相互作用进行协调。通过交换必需的衣壳蛋白编码基因片段，我们确定多价相互作用是由外衣壳蛋白σ3和衣壳转塔蛋白λ2介导的。使用无法结合 NRP1 的衣壳突变体，我们发现 NRP1 有助于呼肠孤病毒在小鼠中的传播和神经毒力。总的来说，我们的结果表明 NRP1 是呼肠孤病毒的进入受体，并揭示了 NRP 促进病毒进入和发病机制的机制。