526 The cutaneous deviant staphylococcus epidermidis induces skin injury via secretion of phenol-soluble modulins

Our group has challenged the concept that S. epidermidis (SE) is only a beneficial commensal microbe by showing when skin colonization of SE increases, it promotes inflammation through production protease EcpA. Analysis genome revealed encodes 4 genes homologous to α-type phenol soluble modulin (PSM) toxic peptide made aureus (SA), thus suggesting another mechanism which can harm skin. Principle component analysis RNA-Seq data from primary keratinocytes (nHEKs) treated with synthetic PSM peptides PSMα, PSMδ, PSMε and δ-toxin (hld) transcriptional response most PSMs was similar SA PSMα3 but PSMα like untreated controls. Induction in IL-17 pathway including CXCL1, CXCL2, CXCL5, CXCL8 (IL8), CCL20, TRAF6, IL-1B, TNFa were observed validated qPCR. Next, isogenic mutants constructed for individual IL-8 release measured ELISA nHEKs exposed sterile-filtered supernatants wild-type (WT) or mutant isolates. PSMδ deletions decreased greater than 50% while double knockout prevented majority cytokine above baseline (IL-8 pg/mL: WT=1752+/-428; Δpsmδ=642+/-100; Δpsmε=1413+/-122; Δhld=724+/-163; ΔpsmδΔhld=397+/-44). To elucidate this we next examined nHEK LDH role activation cell surface GPCR receptors. inhibited inhibitor pertussis toxin prior Control=2004+/-453; Pertussis toxin:984+/-81). also occurred dose-dependent manner after exposure PSMs. These reveal novel driving via both cytolytic stimulation pathways provide further evidence acts as pathogen if enabled produce