Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Nature. 2020 Jul;583(7817):615-619. doi: 10.1038/s41586-020-2369-7. Epub 2020 Jun 3.
Pneumonia resulting from infection is one of the leading causes of death worldwide. Pulmonary infection by the respiratory syncytial virus (RSV) is a large burden on human health, for which there are few therapeutic options. RSV targets ciliated epithelial cells in the airways, but how viruses such as RSV interact with receptors on these cells is not understood. Nucleolin is an entry coreceptor for RSV and also mediates the cellular entry of influenza, the parainfluenza virus, some enteroviruses and the bacterium that causes tularaemia. Here we show a mechanism of RSV entry into cells in which outside-in signalling, involving binding of the prefusion RSV-F glycoprotein with the insulin-like growth factor-1 receptor, triggers the activation of protein kinase C zeta (PKCζ). This cellular signalling cascade recruits nucleolin from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. We find that inhibiting PKCζ activation prevents the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduces viral replication and pathology in RSV-infected mice. These findings reveal a mechanism of virus entry in which receptor engagement and signal transduction bring the coreceptor to viral particles at the cell surface, and could form the basis of new therapeutics to treat RSV infection.
由感染引起的肺炎是全球主要死因之一。呼吸道合胞病毒（RSV）引起的肺部感染对人类健康造成了巨大负担，但目前治疗选择有限。RSV 靶向气道中的纤毛上皮细胞，但 RSV 等病毒如何与这些细胞上的受体相互作用尚不清楚。核仁素是 RSV 的进入核心受体，也介导流感、副流感病毒、某些肠道病毒和引起土拉菌病的细菌进入细胞。在这里，我们展示了 RSV 进入细胞的一种机制，其中涉及到外到内信号，包括 RSV-F 糖蛋白与胰岛素样生长因子-1 受体的预融合结合，触发蛋白激酶 C ζ（PKCζ）的激活。这个细胞信号级联反应将核仁素从细胞的核内招募到质膜，在那里它也与病毒粒子上的 RSV-F 结合。我们发现，抑制 PKCζ 的激活可以防止核仁素在气道类器官培养物中向 RSV 颗粒的运输，并减少 RSV 感染小鼠中的病毒复制和病理学。这些发现揭示了一种病毒进入的机制，其中受体结合和信号转导将核心受体带到细胞表面的病毒颗粒上，这可能成为治疗 RSV 感染的新疗法的基础。
