Dermatophytes activate skin keratinocytes via mitogen-activated protein kinase signaling and induce immune responses.

Rebecca R Achterman,Adam R Smith,Kris M Blair,David L Moyes,Theodore C White,Selvam Thavaraj,Julian R Naglik,G S Deepe

doi:10.1128/iai.02776-14

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.

Highlights

Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts
Utilizing a combination of organotypic epidermal models and primary keratinocytes, we identified mitogen-activated protein kinase (MAPK) signaling as a key pathway activated by dermatophytes, leading to the expression of the c-Fos transcription factor and cytokine induction
Infection with the M. gypseum geophile generally induced higher levels of damage than the anthropophiles (T. rubrum, T. tonsurans) or zoophiles (T. equinum, M. canis), consistent with its role as a more virulent dermatophyte [14]. This might explain why certain cytokines, notably IL1␤, were detected at significantly higher levels from epidermal tissues inoculated with M. gypseum than from those inoculated with most other dermatophytes and the uninfected control

Summary

Introduction

Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts. 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. 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. Infections were performed with anthropophilic (Trichophyton rubrum, Trichophyton tonsurans), geophilic (Microsporum gypseum), and zoophilic (Trichophyton equinum, Microsporum canis) dermatophytes, using the five dermatophyte strains whose genome sequences were recently released with annotation [8] The abilities of these dermatophytes to invade, cause tissue damage, and induce proinflammatory cytokines were compared. We determined whether different morphological forms of the dermatophyte Trichophyton equinum differentially activated cell signaling pathways and host transcription factors

Methods

Results

Conclusion