Human keratinocytes and fibroblasts coordinate early cutaneous innate defenses against Candida auris

Candida auris is an emerging fungal pathogen with a remarkable ability to persist on human skin, but how structural skin cells respond to colonization is unclear. We used ex vivo human skin models, together with primary keratinocytes and fibroblasts, to characterize epithelial and stromal responses to C auris compared with responses to C albicans. C auris formed biofilms and induced a wound-model-dependent pattern of cytokine secretion dominated by IL-1β and IL-6, yet caused minimal epithelial damage and modest reductions in leukocyte viability. RNA sequencing revealed complementary but cell-type-specific responses. Keratinocytes and fibroblasts both amplified a proinflammatory IL-6/CXCL8 response, whereas keratinocytes additionally upregulated antimicrobial genes such as RNASE7, TSLP, DEFB103A (encoding human β-defensin 3), and the neutrophil-recruiting chemokines CXCL2 and CXCL3. Fibroblasts further induced CCL28, supporting T-cell recruitment, alongside transcriptional programs associated with tissue remodeling. Recombinant RNase 7 and short-form TSLP directly inhibited C auris growth in vitro in a dose-dependent manner. Together, these findings identify keratinocytes as epithelial sentinels that integrate inflammatory and antimicrobial defenses against skin-tropic C auris and suggest that fibroblast-driven cytokine amplification and, especially, antimicrobial peptides from within the skin barrier may provide therapeutic targets to limit C auris skin colonization.