From the Department of Internal Medicine, Carver College of Medicine and.
J Biol Chem. 2014 Mar 14;289(11):7537-46. doi: 10.1074/jbc.M113.510594. Epub 2014 Feb 4.
Despite being a major health problem, respiratory syncytial virus (RSV) infections remain without specific therapy. Identification of novel host cellular responses that play a role in the pathogenesis of RSV infection is needed for therapeutic development. The endoplasmic reticulum (ER) stress response is an evolutionarily conserved cellular signaling cascade that has been implicated in multiple biological phenomena, including the pathogenesis of some viral infections. In this study, we investigate the role of the ER stress response in RSV infection using an in vitro A549 cell culture model. We found that RSV infection induces a non-canonical ER stress response with preferential activation of the inositol-requiring enzyme 1 (IRE1) and activated transcription factor 6 (ATF6) pathways with no concomitant significant activation of the protein kinase R-like ER kinase (PERK) pathway. Furthermore, we discovered that IRE1 has an inhibitory effect on RSV replication. Our data characterize, for the first time, the nature of the ER stress response in the setting of RSV infection and identify the IRE1 stress pathway as a novel cellular anti-RSV defense mechanism.
尽管呼吸道合胞病毒 (RSV) 感染是一个主要的健康问题，但目前仍缺乏特异性治疗方法。为了开发治疗方法，需要确定在 RSV 感染发病机制中起作用的新型宿主细胞反应。内质网 (ER) 应激反应是一种进化上保守的细胞信号级联反应，与多种生物学现象有关，包括某些病毒感染的发病机制。在这项研究中，我们使用体外 A549 细胞培养模型研究了 ER 应激反应在 RSV 感染中的作用。我们发现 RSV 感染诱导非典型 ER 应激反应，优先激活肌醇需求酶 1 (IRE1) 和激活转录因子 6 (ATF6) 途径，而蛋白激酶 R 样内质网激酶 (PERK) 途径没有伴随明显激活。此外，我们发现 IRE1 对 RSV 复制具有抑制作用。我们的数据首次描述了 RSV 感染时 ER 应激反应的性质，并确定 IRE1 应激途径是一种新型的细胞抗 RSV 防御机制。
