Novel Gene Signatures Observed in the Nonlesional Skin from European American Atopic Dermatitis Subjects Who Are Colonized with Staphyloccoccus Aureus

Rationale: Atopic dermatitis (AD) is characterized by a dysregulation of immune and barrier genes. AD can be subphenotyped based on the presence or absence of S. aureuscolonization.  Our objective was to determine whether the gene expression profile in the skin differs between these groups.  We focused on nonlesional skin to identify intrinsic abnormalities that are not altered by lesional inflammation. 

Methods: RNA-sequencing (RNA-seq) was performed on biopsies taken from nonlesional, non-sunexposed upper extremity skin obtained from 10 S. aureus colonized (ADStaph+), 10 non-colonized (ADStaph-) AD subjects and 10 nonatopic (NA) Staph- controls. We report differentially expressed genes based on a false discovery rate (FDR) q-value≤0.05 using EdgeR. Gene ontology analysis was performed using the Gene Set Enrichment Analysis (GSEA) to identify KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. 

Results: RNA-seq analysis revealed a distinct transcriptional profile in ADStaph+ subjects compared to ADStaph- subjects, which were not identified in AD (Staph+ and Staph-) vs NA. Forty-seven genes were dysregulated with 40 up-regulated and 7 down-regulated in ADStaph+.  Four of the 40 genes are strongly linked to Th2 inflammation (CCL18, POSTN, CCL13, CCL26). GSEA revealed 20 KEGG pathways (Familywise-error rate; P<0.04) with cytokine/cytokine receptor, T cell receptor signaling, and chemokine signaling being the most over-represented. Validation studies are underway. 

Conclusions: Our findings demonstrate a dysregulation of inflammatory genes, enriched for expression of Th2 pathway genes, in the nonlesional skin of ADStaph+ subjects. The challenge will be to determine whether this is responsible for or the consequence of bacterial colonization and/or disease severity.