Utilization of an in vitro biofabricated 3D skin as a pathological model of cutaneous candidiasis

Candida albicans is an opportunistic fungal infectious agent that can cause cutaneous candidiasis in humans. Biofilms formation of C. albicans is thought to be the major cause of antifungal drug resistance. Despite numerous studies conducted on C. albicans biofilms, a comprehensive understanding of how C. albicans biofilms induced cutaneous candidiasis in humans and the development of a more effective targeted therapy remain poorly investigated. Available animal models of cutaneous candidiasis and in vitro human skin cell cultures do not fully reflect the actual human skin microenvironment or the disease pathogenesis. We investigated the molecular pathology of C. albicans infection using an in vitro biofabricated 3D skin. This in vitro biofabricated 3D skin comprises a fully humanized three-dimensional (3D) skin equivalent, consisting of a stratified terminally differentiated epidermis and an underlying dermal compartment. Antifungal drug susceptibility testing, histological and electron microscopy study, biofilms study, and pro-inflammatory cytokines analysis were conducted in C. albicans infected skin. Histological results revealed that C. albicans covered and produced biofilm on the in vitro biofabricated 3D skin, invading the skin compartments including epidermis and dermis. Elevation of proinflammatory cytokines including MMP-9, IL-1β, TNF-α, and IL-5 were examined in the C. albicans infected skin. However, treatment with itraconazole reduced the pathology of C. albicans infection. This study provides an alternative pathological model of cutaneous candidiasis, which can physiologically represent a close-up event during C. albicans. Moreover, it is rapid, cost-effective, and reproducible of the in vitro biofabricated 3D skin model, and may further highlight the importance of utilizing in vivo-like conditions to improve high-throughput screening for drug discovery against several antifungal drug resistant pathogens.