Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition

Chronic oxidative injury produced by airway disease triggers TGFβ-mediated epigenetic reprogramming known as the epithelial-mesenchymal transition (EMT). We observe that EMT silences protective mucosal interferon (IFN)-I/-III production associated with enhanced rhinovirus (RV) and respiratory syncytial virus(RSV) replication. Mesenchymal transitioned cells are defective in inducible interferon regulatory factor (IRF)1 expression by occluding RelA and IRF3 access to the promoter. IRF1 is necessary for 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; our study demonstrates how airway remodeling/fibrosis is associated with a defective mucosal antiviral response through ZEB1-initiated epigenetic silencing.