Identification of novel gene signatures in patients with atopic dermatitis complicated by eczema herpeticum

Background: A subset of patients with atopic dermatitis (AD) is prone to disseminated herpes simplex virus (HSV) infection, i.e. eczema herpeticum (ADEH+). Biomarkers that identify ADEH+ are lacking. Objective: To search for novel ADEH+ gene signatures in peripheral blood mononuclear cells (PBMCs). Methods: A RNA-sequencing (RNA-seq) approach was applied to evaluate global transcriptional changes using PBMCs from ADEH+ and AD without a history of EH (ADEH-). Candidate genes were confirmed by qPCR or ELISA. Results: ADEH+ PBMCs had distinct changes to the transcriptome when compared to ADEH- PBMCs following HSV-1 stimulation: 792 genes were differentially expressed at a false discovery rate (FDR) < 0.05 (ANOVA), and 15 type I and type III interferon (IFN) genes were among the top 20 most down-regulated genes in ADEH+. We further validated that IFN-α and IL-29 mRNA and protein levels were significantly decreased in HSV-1 stimulated PBMCs from ADEH+ compared to ADEH- and normal. Ingenuity pathway analysis (IPA) demonstrated that the up-stream regulators of type I and type III IFNs, IRF3 and IRF7 was significantly inhibited in ADEH+ based on the down-regulation of their target genes. Furthermore, we found that gene expression of IRF3 and IRF7 were significantly decreased in HSV-1 stimulated PBMC from ADEH+ subjects. Conclusions: PBMCs from ADEH+ have a distinct immune response following HSV-1 exposure compared to ADEH- . Inhibition of the IRF3 and IRF7 innate immune pathways in ADEH+ may be the important mechanisms for increased susceptibility to disseminated viral infection. Expression profiles of PBMCs were taken from 5 AD patients with a history of disseminated herpes simplex virus (HSV) infection, i.e. eczema herpeticum (ADEH+) and 6 AD patients who don’t have a history of disseminated HSV infection (ADEH-). PBMC samples from each subject were divided in two and were treated with and without HSV-1 virus for 21 hours before processing for total RNA.