Membrane transporter proteins are involved in Trichophyton rubrum pathogenesis

Abstract

Trichophyton rubrum is a dermatophyte responsible for the majority of human superficial mycoses. The functional expression of proteins important for the initial step and the maintenance of the infection process were identified previously in T. rubrum by subtraction suppression hybridization after growth in the presence of keratin. In this study, sequences similar to genes encoding the multidrug-resistance ATP-binding cassette (ABC) transporter, copper ATPase, the major facilitator superfamily and a permease were isolated, and used in Northern blots to monitor the expression of the genes, which were upregulated in the presence of keratin. A sequence identical to the TruMDR2 gene, encoding an ABC transporter in T. rubrum, was isolated in these experiments, and examination of a T. rubrum DTruMDR2 mutant showed a reduction in infecting activity, characterized by low growth on human nails compared with the wild-type strain. The high expression levels of transporter genes by T. rubrum in mimetic infection and the reduction in virulence of the DTruMDR2 mutant in a disease model in vitro suggest that transporters are involved in T. rubrum pathogenicity.

Potential of Ergosterol Synthesis Inhibitors To Cause Resistance or Cross-Resistance in Trichophyton rubrum

“…The resistance of dermatophytes to inhibiting agents involves the participation of target-enzyme modifiers and overexpression of ATP-binding cassette (ABC) transporters and stress-related proteins (23). In T. rubrum, two ABC transporters, TruMDR1 and TruMDR2, were identified as responsible for resistance to various antifungal drugs, such as ITC and TRB (24,25). Candida albicans clinical isolates resistant to azole compounds and overexpressing the ABC transporter gene products CDR1 and CDR2 are less susceptible to the morpholine derivative AMF (26).…”

Majocchi’s Granuloma (Dermatophytic Granuloma): Updated Therapeutic Options

“…T. rubrum secretes many proteolytic enzyme-like metallocarboxypeptidase, serine carboxipeptidase with a glycosylphosphatidilinositol anchor that may contribute to fungal virulence [34,35], and hemolysins in T. verrucosum infection. [3] Dermatophytes evade host immune system by several mechanisms: (1) cell wall glycoproteins, endoproteases, and exoproteases isolated from T. rubrum and M. canis; (2) producing the lysine motive binding domain by securing fragments of chitin or even producing mannans associated with glycoprotein; (3) provoking the release of anti-inflammatory cytokines and TLR blockade (mainly TLR2), and therefore leading to (4) generation of T regulatory cells with strong immunosuppressive potential; and thus (5) the blockade of Th1 response (by suppressing the activity of keratinocytes and dendritic cells), and activating Th2 response which is unable to control fungal infection, leading to chronic inflammation as seen in MG [36,37,38…”

Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes

“…ATP-binding cassette (ABC) transporters are involved in a variety of processes such as nutrient uptake, pathogenesis, and efflux pumping of structurally unrelated drugs with different modes of action (Jones et al, 2014;Maranhão et al, 2009). They act effectively in drug efflux, decreasing the accumulation of cytotoxic agents in the intracellular milieu, thus playing a significant role in multidrug resistance (MDR) mechanisms (Higgins, 1992;Wirsching et al, 2000).…”

“…Genetic analysis of the T. interdigitale mdr2 knockout (Dmdr2) strain showed that MDR2 modulates the susceptibility to terbinafine (Fachin et al, 2006). Furthermore, high transcription levels of the mdr2 gene in T. interdigitale during mimetic infection (Maranhão et al, 2007), and reduced virulence in Dmdr2 mutants in an ex vivo infection model, suggest that this transporter is also involved in fungal pathogenicity (Maranhão et al, 2009). In Candida albicans, loss-of-function or inhibition of one ABC transporter activates different transporters, resulting in compensatory effects that modulate the efflux of antifungal drugs (Sanglard et al, 1997).…”