The Transcriptional Profile of Trichophyton rubrum Co-Cultured with Human Keratinocytes Shows New Insights about Gene Modulation by Terbinafine.

Monise Fazolin Petrucelli,Ana Lúcia Fachin,Wilson Araújo Silva,Pablo Rodrigo Sanches,Josie Budag Matsuda,Kamila Peroni,Rene Oliveira Beleboni,Mozart Marins,Nilce Maria Martinez-Rossi

doi:10.3390/pathogens8040274

Abstract

The dermatophyte Trichophyton rubrum is the main causative agent of dermatophytoses worldwide. Although a superficial mycosis, its incidence has been increasing especially among diabetic and immunocompromised patients. Terbinafine is commonly used for the treatment of infections caused by dermatophytes. However, cases of resistance of T. rubrum to this allylamine were reported even with the efficacy of this drug. The present study is the first to evaluate the effect of terbinafine using a co-culture model of T. rubrum and human keratinocytes, mimicking a fungus-host interaction, in conjunction with RNA-seq technique. Our data showed the repression of several genes involved in the ergosterol biosynthesis cascade and the induction of genes encoding major facilitator superfamily (MFS)- and ATP-binding cassette superfamily (ABC)-type membrane transporter which may be involved in T. rubrum mechanisms of resistance to this drug. We observed that some genes reported in the scientific literature as candidates of new antifungal targets were also modulated. In addition, we found the modulation of several genes that are hypothetical in T. rubrum but that possess known orthologs in other dermatophytes. Taken together, the results indicate that terbinafine can act on various targets related to the physiology of T. rubrum other than its main target of ergosterol biosynthetic pathway.

Highlights

Dermatophytoses are superficial infections of keratinized tissues that are caused by a group of filamentous fungi, called dermatophytes [1]
Terbinafine, an antifungal agent of the allylamine class, is commonly used for the treatment of infections caused by dermatophytes, with the highest activity being observed against species of the genus Trichophyton, Microsporum, and Epidermophyton [9]
Low-quality reads were removed and the remaining reads were aligned to the T. rubrum reference genome (CBS 118892) of the Broad Institute’s Dermatophyte

Summary

Introduction

Dermatophytoses are superficial infections of keratinized tissues that are caused by a group of filamentous fungi, called dermatophytes [1]. Among these dermatophytes, Trichophyton rubrum is the main causative agent of dermatophytoses in the world [2,3]. Knowledge of the molecular mechanisms involved in the fungus-host interaction is still limited because of technical difficulties of the available models that mimic this interaction New models such as co-culture of T. rubrum with keratinocyte cell lines and culture media containing keratin and elastin were introduced recently as strategies to evaluate compounds with antifungal activities [6,7,8]. The inhibition of the early steps of this pathway triggers fungicidal activity against susceptible species, filamentous fungi [11]

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Conclusion