Chronic oxidative injury produced by airway disease triggers a transforming growth factor-β (TGF-β)-mediated epigenetic reprogramming known as the epithelial-mesenchymal transition (EMT). We observe that EMT silences protective mucosal interferon (IFN)-I and III production associated with enhanced rhinovirus (RV) and respiratory syncytial virus (RSV) replication. Mesenchymal transitioned cells are defective in inducible interferon regulatory factor 1 (IRF1) expression by occluding RelA and IRF3 access to the promoter. IRF1 is necessary for the expression of type III IFNs (IFNLs 1 and 2/3). Induced by the EMT, zinc finger E-box binding homeobox 1 (ZEB1) binds and silences IRF1. Ectopic ZEB1 is sufficient for IRF1 silencing, whereas ZEB1 knockdown partially restores IRF1-IFNL upregulation. ZEB1 silences IRF1 through the catalytic activity of the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), forming repressive H3K27(me3) marks. We observe that IRF1 expression is mediated by ZEB1 de-repression, and our study demonstrates how airway remodelling/fibrosis is associated with a defective mucosal antiviral response through ZEB1-initiated epigenetic silencing.

中文翻译：

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IRF1的表观遗传沉默在上皮到间充质过渡中失调了III型干扰素对呼吸道病毒感染的反应。

气道疾病引起的慢性氧化损伤触发转化生长因子-β（TGF-β）介导的表观遗传重编程，称为上皮-间质转化（EMT）。我们观察到，EMT使与增强的鼻病毒（RV）和呼吸道合胞病毒（RSV）复制相关的保护性粘膜干扰素（IFN）-I和III产生沉默。间充质转化细胞通过阻止RelA和IRF3进入启动子而在诱导型干扰素调节因子1（IRF1）表达方面存在缺陷。IRF1是表达III型IFN（IFNL 1和2/3）所必需的。由EMT诱导，锌指E-box结合同源盒1（ZEB1）结合并使IRF1沉默。异位ZEB1足以使IRF1沉默，而ZEB1敲低可部分恢复IRF1-IFNL的上调。ZEB1通过zeste 2聚梳抑制复合物2亚基（EZH2）的增强剂的催化活性使IRF1沉默，形成抑制性H3K27（me3）标记。我们观察到IRF1表达是由ZEB1抑制介导的，我们的研究表明气道重塑/纤维化如何通过ZEB1启动的表观遗传沉默与不良的粘膜抗病毒反应有关。