Background Superficial cutaneous infection caused by the zoophilic dermatophyte Trichophyton benhamiae is often associated with a highly inflammatory immune response. As non‐professional immune cells, epidermal keratinocytes and dermal fibroblasts contribute to the first line of defence by producing pro‐inflammatory cytokines and antimicrobial peptides (AMP). Objective Purpose of this study was to gain a deeper understanding of the pathogenesis and the fungal–host interaction as not much is known about the innate immune response of these cutaneous cells against T. benhamiae. Methods Using a dermatophytosis model of fibroblasts and keratinocytes incubated with T. benhamiae DSM 6916, analyses included determination of cell viability and cytotoxicity, effects on the innate immune response including expression and secretion of pro‐inflammatory cytokines/chemokines and expression of AMP, as well as alterations of genes involved in cell adhesion. Results Trichophyton benhamiae DSM 6916 infection led to severe cell damage and direct induction of a broad spectrum of pro‐inflammatory cytokines and chemokines in both cutaneous cells. Only keratinocytes differentially up‐regulated AMP genes expression after T. benhamiae DSM 6916 infection. Expression of AMPs in fibroblasts was not inducible by fungal infection, whereas their absences potentially contributed to a continuous increase in the fungal biomass on fibroblasts, which in turn was reduced in keratinocytes possibly due to the antimicrobial actions of induced AMPs. On mRNA level, T. benhamiae DSM 6916 infection altered cell–cell contact proteins in keratinocytes, indicating that targeting specific cell–cell adhesion proteins might be part of dermatophytes’ virulence strategy. Conclusion This study showed that in addition to immune cells, keratinocytes and fibroblasts could participate in antimicrobial defence against an exemplary infection with T. benhamiae DSM 6916.
Exceedingly virulent pathogens and growing antimicrobial resistances require new therapeutic approaches. The zoophilic dermatophyte Trichophyton benhamiae causes highly inflammatory, cutaneous fungal infections. Recently, it could be shown that the plant-derived alkaloid tryptanthrin (TRP) exhibits strong anti-microbial activities against yeasts and dermatophytes. The aim of this study was to analyse the bioactivity of TRP under infectious conditions using an in-vitro dermatophytosis model employing fibroblasts and keratinocytes infected with T. benhamiae DSM6916. Analyses comprised determination of cell viability, effects on the innate immune response including expression and secretion of pro-inflammatory cytokines/chemokines as well as expression of various antimicrobial peptides (AMP), toll-like receptor (TLR) 2 and proliferation marker MKI67. T. benhamiae caused severe inflammation in the cutaneous cell models. TRP almost fully prevented T. benhamiae-derived damage of dermal fibroblasts and substantially reduced it in epidermal keratinocytes. A distinct down-regulation of the expression and secretion of pro-inflammatory cytokines was observed. Further, TRP promoted AMP expression, especially of HBD2 and HBD3, in keratinocytes even without fungal presence. This study provides crucial evidence that TRP is not only a strong antifungal agent but also potentially modulates the innate immune response. This makes it interesting as a natural antimycotic drug for adjuvant treatment and prevention of fungal re-infection. Dermatophytoses present a serious public health issue affecting 20-25% of the world's population 1. Especially zoophilic dermatophytes often cause acute, highly inflammatory, cutaneous infections in humans 2,3. In Germany the guinea pig-associated dermatophyte Trichophyton benhamiae pertain to one of the most common cause for fungal infections especially among children and adolescents 4,5. Due to the growing mobility and migration, a pathogen shift with an emergent incidence of new fungi can be observed 6 , which in turn leads to an increasing application of broad-spectrum antimycotics. A new more virulent and potentially contagious Trichophyton mentagrophytes strain was recently isolated in India. Its origin seems to be unknown, but its occurrence is dramatically on the rise even replacing T. rubrum as the most common species causing superficial dermatophytosis in India 7,8. With the rising prevalence of fungal infections, the emerging antimycotic resistance 9,10 as well as the appearance of new and highly virulent pathogens novel therapeutic approaches are required. Hence, it is of great interest to find alternative, natural, antimycotically effective agents. In addition to exhibiting antimicrobial properties, it would be worthwhile if they also potentially influenced the immune response by e.g. promoting the defence and immune responses of cells against invading pathogens. Plants possess secondary metabolites that are anti-microbial compounds accumulating in regions of pathogenic infection. These in...
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