Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1

Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance cells virus infections. Activated transcription factors in conjunction chromatin remodelers induce epigenetic changes reprogram responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven confers increased viral and bacterial infections allergen challenges. Here, we tested hypothesis repair protein OGG1 recognizes (8-oxoGua) promoters modulating expression. We found functional inhibition, genetic ablation, inactivation by post-translational modification significantly augment IFN-λ epithelial infected human respiratory syncytial (RSV). Mechanistically, bound 8-oxoGua proximity interferon response elements, which inhibits IRF3/IRF7 NF-κB/RelA occupancy, while promoting suppressor NF-κB1/p50-p50 homodimer binding IFN-λ2/3 promoter. In a mouse model bronchiolitis induced RSV infection, ablation small molecule inhibitor (TH5487) enhances production, decreases immunopathology, neutrophilia, antiviral protection. These findings suggest ROS-generated mark via its reader serves as homeostatic thresholding factor Pharmaceutical targeting activity may have clinical utility response.