Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Center for Pediatric Pulmonary Medicine, Cleveland Clinic Children's, Cleveland, Ohio 44195, USA.
J Cell Sci. 2022 Aug 15;135(16). doi: 10.1242/jcs.259871. Epub 2022 Aug 16.
Respiratory syncytial virus (RSV) infection is the leading cause of acute lower respiratory tract infection in young children worldwide. Our group recently revealed that RSV infection disrupts the airway epithelial barrier in vitro and in vivo. However, the underlying molecular pathways were still elusive. Here, we report the critical roles of the filamentous actin (F-actin) network and actin-binding protein cortactin in RSV infection. We found that RSV infection causes F-actin depolymerization in 16HBE cells, and that stabilizing the F-actin network in infected cells reverses the epithelial barrier disruption. RSV infection also leads to significantly decreased cortactin in vitro and in vivo. Cortactin-knockout 16HBE cells presented barrier dysfunction, whereas overexpression of cortactin protected the epithelial barrier against RSV. The activity of Rap1 (which has Rap1A and Rap1B forms), one downstream target of cortactin, declined after RSV infection as well as in cortactin-knockout cells. Moreover, activating Rap1 attenuated RSV-induced epithelial barrier disruption. Our study proposes a key mechanism in which RSV disrupts the airway epithelial barrier via attenuating cortactin expression and destabilizing the F-actin network. The identified pathways will provide new targets for therapeutic intervention toward RSV-related disease. This article has an associated First Person interview with the first author of the paper.
呼吸道合胞病毒 (RSV) 感染是全球儿童急性下呼吸道感染的主要原因。我们的团队最近发现 RSV 感染会破坏气道上皮屏障的体外和体内。然而，其潜在的分子途径仍不清楚。在这里，我们报告丝状肌动蛋白 (F-actin) 网络和肌动蛋白结合蛋白 cortactin 在 RSV 感染中的关键作用。我们发现 RSV 感染会导致 16HBE 细胞中的 F-actin 解聚，而在感染细胞中稳定 F-actin 网络可逆转上皮屏障的破坏。RSV 感染还会导致体外和体内 cortactin 显著减少。Cortactin 敲除的 16HBE 细胞表现出屏障功能障碍，而 cortactin 的过表达则可保护上皮屏障免受 RSV 的侵害。Rap1（具有 Rap1A 和 Rap1B 两种形式）的活性，作为 cortactin 的下游靶点之一，在 RSV 感染后以及 cortactin 敲除细胞中均下降。此外，激活 Rap1 可减轻 RSV 诱导的上皮屏障破坏。我们的研究提出了一个关键机制，即 RSV 通过削弱 cortactin 的表达和破坏 F-actin 网络来破坏气道上皮屏障。所鉴定的途径将为针对 RSV 相关疾病的治疗干预提供新的靶点。本文附有该论文第一作者的相关第一人称采访。
