RSV-induced Epigenetic regulation of DC via H3K4 demethylase KDM5b

Abstract

Abstract Immune regulation by epigenetic mechanisms has become an intense area of research. The concept that our immune system responses are influenced by environmental factors including microorganisms, pollution, and pathogen exposure is important as a backdrop for understanding disease progression. We previously observed an upregulation of KDM5B, an H3K4 demethylase, following RSV infection of DCs that regulates key innate cytokines, Type I IFN and TNF. As H3K4 tri-methylation is an activating mark, this demethylase should act as a transcriptional repressor to specific gene targets. Our in vitro and transcriptomic data shows genomic ablation of KDM5B in DC leads to greater antiviral response following RSV or TLR stimulation. This includes upregulation of type I IFN and downstream elements such as Cxcl10, Oasl1, and Mx2 genes. While more than 500 genes appear to be regulated in the KDM5b KO DC after RSV infection compared to WT DC, specific transcriptional regulation linked to type I responses were indicated. Utilizing the transcription factor prediction tool BART reveals IRF3, IRF7, and STAT1 as regulatory factors for the differentially expressed genes following TLR re-stimulation of RSV infected KDM5B-KO DC. To further extend these findings to an in vivo setting, KDM5b-CD11c-CRE+ mice were infected by RSV and, after 3 weeks, re-infected with RSV. Compared to KDM5b sufficient mice, there was a reduction in secondary RSV infection induced pathology and altered immune mediators.