Dermatophytes Activate Skin Keratinocytes via Mitogen-Activated Protein Kinase Signaling and Induce Immune Responses

Rebecca R. Achterman,S* David L. Moyes,b Selvam Thavaraj,b Adam R. Smith,c Kris M. Blair,S*, Theodore C. White,c Julian R. Naglikb, Seattle Biomedical Research Institute, Seattle, Washington, USA"; Mucosal and Salivary Biology Division, King's College London Dental Institute, King's College London, London, United Kingdomb; Division of Cell Biology and Biochemistry, University of Missouri at Kansas City, Kansas City, Missouri, USN

Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts. However, the host mechanisms that regulate innate immune responses against these fungi are largely unknown. Here, we utilized commercially available epidermal tissues and primary keratinocytes to assess (i) damage induction by anthropophilic, geophilic, and zoophilic dermatophyte strains and (ii) the keratinocyte signaling pathways, transcription factors, and proinflammatory responses induced by a representative dermatophyte, Trichophyton equinum. Initially, five dermatophyte species were tested for their ability to invade, cause tissue damage, and induce cytokines, with Microsporum gypseum inducing the greatest level of damage and cytokine release. Using T. equinum as a representative dermatophyte, we found that the mitogen-activated protein kinase (MAPK) pathways were predominantly affected, with increased levels of phospho-p38 and phospho-Jun N-terminal protein kinase (JNK) but decreased levels of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2). Notably, the NF-κB and PI3K pathways were largely unaffected. T. equinum also significantly increased expression of the AP-1-associated transcription factor, c-Fos, and the MAPK regulatory phosphatase, MKP1. Importantly, the ability of T. equinum to invade, cause tissue damage, activate signaling and transcription factors, and induce proinflammatory responses correlated with germination, indicating that germination may be important for dermatophyte virulence and host immune activation.


EpiDerm, EPI-200-AFAB, dermatophytes, fungal infection, keratinocyte signaling pathways, transcription factors, proinflammatory response, LDH, IL-8, IL-1b, timp1, mmp1, cox2, c-fos, MAPK pathway-associated regulator, MKP1, IL-6, IL-10, TNF-α, IL-12p70, GM-CSF

Materials Tested

Trichophyton rubrum, Trichophyton tonsurans , Trichophyton equinum , Microsporum canis , Microsporum gypseum

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