The composition of the skin microbiome varies widely among individuals sampled at the same body site. A key question is which molecular factors determine strain-level variability within sub-ecosystems of the skin. We used a genomics-guided approach to identify an antibacterial biosynthetic gene cluster inCutibacterium acnes(formerlyPropionibacterium acnes) that is widely distributed across individuals and skin sites. Experimental characterization of this cluster enabled the identification of a new thiopeptide antibiotic, cutimycin. Analysis of individual human skin hair follicles showed that cutimycin is an important factor regulating colonization resistance againstStaphylococcusspecies.One Sentence SummaryCutimycin, a thiopeptide antibiotic produced by a widespread skin commensal, reducesStaphylococcuscolonization of human follicles.
An important role of keratinocyte (KC) is to serve as a barrier against environmental stimuli including microbial infections. S. aureus acts as pathobiont on human skin often worsening atopic dermatitis, while normally colonizing in nasal cavity and gut. Therefore, to address how S. aureus behaves as pathobiont in skin through KC activation, we first examined the role of MyD88 signaling in KC. S. aureus were colonized epicutaneously in wild-type (WT), MyD88-/and K14-CreMyd88-/mice. WT mice exhibited severe skin inflammation 7 days after S. aureus colonization, whereas Myd88-/mice showed no skin inflammation. Importantly, K14-CreMyd88-/mice developed dramatically reduced skin inflammation, suggesting the importance of MyD88 in KC. IL-1 family cytokines, upstream mediators of MyD88, are reportedly expressed in KC and trigger skin inflammation. S. aureus-colonized Il1r-/mice showed moderately reduced skin inflammation. In addition, IL-36R-blocking antibody (Ab) treatment in Il1r-/mice further reduced the inflammation, indicating the importance of IL-1 and IL-36. We next examined IL-17 expressions in S. aureus-colonized skin. S. aureuscolonized K14-CreMyd88-/and IL-36R-blocking Ab-injected Il1r-/mice showed dramatically decreased IL-17 expressions compared to WT mice. Additionally, S. aureus-colonized Il17af-/mice showed significantly less skin inflammation. Taken together, IL-17 plays a pivotal role in the skin inflammation. Moreover, we discovered that phenol soluble modulin a (PSMa) from S. aureus induced IL-36 and IL-1 release from primary KC along with inducing cell death in vitro, and psma-deleted S. aureus (LACDpsma) did not induce the skin inflammation in vivo. In conclusion, we identified that PSMa as a key virulence factor in epicutaneous S. aureus-induced skin inflammation through IL-36 and IL-1 release from KC.
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