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

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.

Epidemiology and Diagnostic Perspectives of Dermatophytoses

“…Approximately 28% of these genes have been studied in other dermatophytes but not in T. rubrum , thus contributing to the elucidation of the functions of these genes in this species and of the response mechanisms to antifungal agents. In addition, modulation of different genes with an important role in the biosynthesis and transport of ergosterol, such as ERG1, ERG5, ERG11, CYP51, and CYP61, was demonstrated [ 103 ].…”

Hereditäre Ichthyose und Pilzinfektion: aktuelle Daten zu Pathogenese und Behandlungsstrategien

“…Immunlage des Wirts: Die Wirtsimmunität spielt eine entscheidende Rolle bei Pilzinfektionen, und zellvermittelte Immunreaktionen werden weithin als verantwortlich für die Abwehr von Pilzinfektionen angesehen [43]. Generalisierte Pilzinfektionen der Haut werden typischerweise bei diabetischen oder immungeschwächten Patienten beobachtet [44], während Patienten mit Ichthyose meist immunkompetent sind. Jedoch können Patienten mit Ichthyose atopisch sein [26, 45].…”

“…T. rubrum produziert Substanzen, die die Immunantwort des Wirts schwächen, darunter das Zellwand‐Glykoprotein Mannan, das möglicherweise die Entzündungsreaktion unterdrückt. Dies gilt speziell für atopische Patienten oder Patienten, die anfällig für eine durch Mannan induzierte Unterdrückung der zellvermittelten Immunantwort sind [44]. Mannan kann, insbesondere bei Patienten mit Ichthyose, die Keratinozytenproliferation und den epidermalen Umsatz unterdrücken [42, 46], und die Lymphozytendifferenzierung sowie die proliferative Reaktion auf Mitogene beeinträchtigen [50, 51].…”

Inherited ichthyosis and fungal infection: an update on pathogenesis and treatment strategies

“…Host immune conditions : Host immunity plays a vital role in fungal infections, and cell‐mediated immune responses are widely considered to be responsible for anti‐fungal defenses [43]. Generalized fungal skin infections are typically observed in diabetic or immunocompromised patients [44], while patients with ichthyosis are generally immunocompetent. However, patients with ichthyosis may be atopic [26, 45].…”

“…Immune escape by T. rubrum : T. rubrum is the most common etiologic agent of dermatophytosis, accounting for approximately 80 % of all cases, and is also the most frequently reported pathogen in patients with ichthyoses [49]. T. rubrum produces substances that weaken the host immune response, including the cell‐wall glycoprotein, mannan, which might suppress the inflammatory response, especially in atopic patients or patients susceptible to mannan‐induced suppression of the cell‐mediated immune response [44]. Mannans can suppress keratinocyte proliferation and epidermal turnover, especially in patients with ichthyosis [42, 46], and can impair lymphocyte differentiation and the proliferative response to mitogens [50, 51].…”