title: Dermatophytes activate skin keratinocytes via mitogen-activated protein kinase signaling and induce immune responses.
abstract: 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.
authors: Seattle Biomedical Research Institute, Seattle, Washington, USA.
authors: Rebecca R
authors: RR
authors: Achterman
authors: Mucosal and Salivary Biology Division, King's College London Dental Institute, King's College London, London, United Kingdom.
authors: David L
authors: DL
authors: Moyes
authors: Mucosal and Salivary Biology Division, King's College London Dental Institute, King's College London, London, United Kingdom.
authors: Selvam
authors: S
authors: Thavaraj
authors: Division of Cell Biology and Biochemistry, University of Missouri at Kansas City, Kansas City, Missouri, USA.
authors: Adam R
authors: AR
authors: Smith
authors: Seattle Biomedical Research Institute, Seattle, Washington, USA.
authors: Kris M
authors: KM
authors: Blair
authors: Division of Cell Biology and Biochemistry, University of Missouri at Kansas City, Kansas City, Missouri, USA whitetc@umkc.edu julian.naglik@kcl.ac.uk.
authors: Theodore C
authors: TC
authors: White
authors: Mucosal and Salivary Biology Division, King's College London Dental Institute, King's College London, London, United Kingdom whitetc@umkc.edu julian.naglik@kcl.ac.uk.
authors: Julian R
authors: JR
authors: Naglik
mesh_terms: D003883:Arthrodermataceae / Q000276:immunology* / Q000472:pathogenicity; D002478:Cells, Cultured; D003881:Dermatomycoses / Q000276:immunology*; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000382:microbiology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014249:Trichophyton / Q000276:immunology* / Q000472:pathogenicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1