Human keratinocytes and fibroblasts coordinate innate defenses against *Candida auris* skin colonization

Candida auris is a globally emerging fungal pathogen, notorious for its multidrug resistance and remarkable ability to persist on human skin, contributing to its spread in healthcare settings. Despite its prevalence on cutaneous surfaces, the precise mechanisms by which structural skin cells—namely keratinocytes and fibroblasts—respond to and defend against C. auris colonization remain poorly understood. Current antifungal strategies often target systemic infections, leaving a gap in understanding and developing localized, skin-specific interventions. Elucidating the innate immune contributions of these cells is crucial for identifying novel therapeutic targets to limit skin carriage and transmission.

Researchers employed ex vivo human skin models, alongside primary human keratinocytes and fibroblasts, to characterize the epithelial and stromal responses to C. auris exposure. For comparison, responses to Candida albicans were also assessed. The study design involved exposing these models and cell cultures to the fungal pathogens and subsequently evaluating various immune parameters. Key methods included assessing cytokine secretion patterns, quantifying epithelial damage, and measuring leukocyte viability. Comprehensive gene expression analysis was performed using RNA sequencing to identify cell-type-specific transcriptional programs. Additionally, the direct antifungal activity of recombinant proteins, RNase 7 and short form TSLP, was tested in vitro in a dose-dependent manner against C. auris.

Upon exposure, C. auris readily formed biofilms within the skin models and induced a wound-model-dependent pattern of cytokine secretion, notably dominated by IL-1β and IL-6. Despite this, C. auris caused only minimal epithelial damage and modest reductions in leukocyte viability, suggesting a nuanced host response. RNA sequencing revealed distinct yet complementary cell-type-specific responses. Both keratinocytes and fibroblasts significantly amplified a pro-inflammatory IL-6/CXCL8 response. Keratinocytes, acting as epithelial sentinels, additionally upregulated a suite of antimicrobial genes, including RNASE7, TSLP, DEFB103A (encoding hBD-3), and the neutrophil-recruiting chemokines CXCL2 and CXCL3. Fibroblasts further induced CCL28, a chemokine supporting T cell recruitment, alongside transcriptional programs associated with tissue remodeling. The most compelling finding demonstrated direct antifungal efficacy: > Recombinant RNase 7 and short form TSLP directly inhibited C. auris growth in vitro in a dose-dependent manner, highlighting their potential as therapeutic agents.