LAUSR

Abstract The asthmatic lung is prone to respiratory viral infections that exacerbate the symptoms of the underlying disease. Recent work has suggested that a deficient T‐helper cell type 1 response in early life may lead to these aberrant antiviral responses. To study the development of long‐term dysregulation of innate responses, which is a hallmark of asthma, we investigated whether the inflammatory environment of the airway epithelium can modulate antiviral gene expression via epigenetic mechanisms. We primed AALEB cells, a human bronchial epithelial cell line, with IFN‐&ggr; and IL‐13, and subsequently infected the cells with respiratory syncytial virus (RSV). We then analyzed the expression of innate antiviral genes and their epigenetic markers. Priming epithelial cells with IFN‐&ggr; reduced the RSV viral load. Microarray analysis identified that IFN‐&ggr; priming enhanced retinoic acid‐inducible gene (RIG)‐I mRNA expression, and this expression correlated with epigenetic changes at the RIG‐I promoter that influenced its transcription. Using chromatin immunoprecipitation, we observed a reduction of trimethylated histone 3 lysine 9 at the RIG‐I promoter. Addition of inhibitor BIX‐01294 to this model indicated an involvement of lysine methyltransferase G9a in RIG‐I epigenetic regulation. These data suggest that prior exposure to IFN‐&ggr; may leave an epigenetic mark on the chromatin that enhances airway cells' ability to resist infection, possibly via epigenetic upregulation of RIG‐I. These observations provide further evidence for a crucial role of IFN‐&ggr; in the development of mature antiviral responses within a model of respiratory infection. Further clinical validation is required to determine whether this effect in early life leads to changes in antiviral responses associated with asthma.