Competition between AMP kingdoms in atopic dermatitis leads to depletion of the defense function of the skin microbiome against S. aureus

Most coagulase-negative Staphylococcus(CoNS) strains on healthy human skin produce antimicrobials that kill S. aureus(SA), but these CoNS with antimicrobial activity(CoNS-AM+) are rare on patients with atopic dermatitis (AD). In this study we sought to understand why AD subjects lack CoNS-AM+ and are instead populated by strains without antimicrobial activity(CoNS-AM-). To examine this, strains of CoNS-AM+, CoNS-AM-, or SA were applied to skin of mice with AD-like inflammation induced by ovalbumin (OVA) or psoriasis-like inflammation induced by imiquimod. 24hr after application, CoNS-AM- strains persisted equally well on inflamed skin of either model and on non-inflamed skin of control mice. SA was killed 94-fold more effectively on the imiquimod model than on OVA model(p<0.005). However, CoNS-AM+ died on inflamed skin of both models compared to controls(decrease on OVA by 95%; imiquimod model by 98.5%). A similar response occurred when CoNS-AM+ was applied to humans with AD, where these bacteria were eliminated within 24 hrs from inflamed skin but persisted for 6 days on non-lesional skin. Since both mouse models had induction of cathelicidin (8.7-fold induction by OVA vs 286-fold by imiquimod), we hypothesized that cathelicidin expressed in AD was sufficient to kill CoNS-AM+ due to synergy between the human and the bacterial antimicrobial peptides (AMPs). To test this, a Δlantibiotic mutant (CoNS-AM-) was generated in S. hominis A9 (CoNS-AM+). The Δlantibiotic mutant survived on both inflamed mouse skin models whereas the parental strain could not. The wild type S. hominis A9 was >10.6-fold more sensitive to killing by LL-37 cathelicidin than the Δlantibiotic mutant. The data show that the CoNS-AM+ community is self-destructive in inflammatory conditions where the skin expresses cathelicidin, but in AD the lower level of cathelicidin expression cannot kill SA without help from the microbiome. The combined loss of CoNS-AM+ strains and lower expressed human AMPs explains the severe loss of cutaneous antimicrobial defense in AD.