Isolation of transcripts over-expressed in human pathogen Trichophyton rubrum during growth in keratin

Maranhão, Fernanda Cristina de Albuquerque; Paião, Fernanda Gonzales; Martinez-Rossi, Nilce M.

doi:10.1016/j.micpath.2007.05.006

Cited by 65 publications

(61 citation statements)

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“…In contrast to recent secretome analyses of T. rubrum soy medium cultures (8), we also identified the activation of protease genes MEP1, MEP2, and DPPV, notably, the latter two only during the growth of T. rubrum in keratin-containing medium. Expression of individual protease genes on keratin has also been detected by suppression-subtractive hybridization screens in T. mentagrophytes, i.e., dipeptidyl peptidase V (12) and in T. rubrum, i.e., Sub3, Sub5, Mep3, and Mep4 (19).…”

Section: Discussionmentioning

confidence: 99%

“…In dermatophytes, recent applications of such techniques revealed the transcriptional response of T. rubrum cells in distinct developmental growth phases and in the presence of novel fatty acid synthase inhibitors (16,33). Differential cDNA screening allowed first insights into the response of Trichophyton menta-grophytes and T. rubrum during growth on protein substrates (12,19); nevertheless, the basic mechanisms of adaptation during growth under such conditions need further investigations. The aim of the present study was to analyze a broad gene expression profile by cDNA microarray analysis in T. rubrum cells during keratin utilization.…”

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Gene Expression Profiling in the Human Pathogenic Dermatophyte Trichophyton rubrum during Growth on Proteins

et al. 2009

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Dermatophytes are highly specialized filamentous fungi which cause the majority of superficial mycoses in humans and animals. The high secreted proteolytic activity of these microorganisms during growth on proteins is assumed to be linked to their particular ability to exclusively infect keratinized host structures such as the skin stratum corneum, hair, and nails. Individual secreted dermatophyte proteases were recently described and linked with the in vitro digestion of keratin. However, the overall adaptation and transcriptional response of dermatophytes during protein degradation are largely unknown. To address this question, we constructed a cDNA microarray for the human pathogenic dermatophyte Trichophyton rubrum that was based on transcripts of the fungus grown on proteins. Profiles of gene expression during the growth of T. rubrum on soy and keratin protein displayed the activation of a large set of genes that encode secreted endo-and exoproteases. In addition, other specifically induced factors potentially implicated in protein utilization were identified, including heat shock proteins, transporters, metabolic enzymes, transcription factors, and hypothetical proteins with unknown functions. Of particular interest is the strong upregulation of key enzymes of the glyoxylate cycle in T. rubrum during growth on soy and keratin, namely, isocitrate lyase and malate synthase. This broad-scale transcriptional analysis of dermatophytes during growth on proteins reveals new putative pathogenicityrelated host adaptation mechanisms of these human pathogenic fungi.Dermatophytes are highly specialized fungi which are the most common agents of superficial mycoses in humans and animals (13, 34). Among the human pathogenic dermatophytes, the anthropophilic species Trichophyton rubrum is clinically the most commonly observed. In contrast to most other medically important fungi, dermatophytes are not opportunists but are obligate pathogens, infecting exclusively the skin stratum corneum, nails, or hair. The ability of dermatophytes to degrade and utilize compact hard keratin within such host structures is presumably related to their common secreted keratinolytic activity, which is therefore a major putative virulence attribute of these fungi. Individual endo-and exoproteases secreted by dermatophytes are similar to those of species of the genus Aspergillus. However, in contrast to those of Aspergillus spp., dermatophyte-secreted endoproteases are multiple and members of two large protein families, the subtilisins (Subs) S8 (serine proteases) and the fungalysins M36 (metalloproteases) (see the MEROPS peptidase database, http://merops.sanger.ac.uk) (10, 11). More than 20 genes that encode secreted proteases have been identified in dermatophytes, some of which have been characterized in detail on the molecular level (reviewed in reference 23).In order to better understand the basic mechanisms of protein degradation by dermatophytes, the secretome of different dermatophyte species was previously analyzed during in vitro growt...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Gene Expression Profiling in the Human Pathogenic Dermatophyte Trichophyton rubrum during Growth on Proteins

et al. 2009

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“…It was shown that T. rubrum rapidly responds to changes in neutral pH by modulating its gene expression profile. 27,28 This metabolic machinery allows dermatophytes to use proteins as a source of nutrients in a wide pH spectrum. This makes the complete installation, development and permanence of the dermatophyte in the host tissue possible.…”

Section: Host-dermatophyte Interaction and The Pathogenesis Of Dermatmentioning

confidence: 99%

Dermatófitos: interação patógeno-hospedeiro e resistência a antifúngicos

Peres¹,

Maranhão²,

Rossi

et al. 2010

An. Bras. Dermatol.

156

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Cutaneous mycoses are among the most common infections in humans and have become an important public health issue because they cause invasive infections in immunocompromised patients. During the infectious process, dermatophyte-host interactions trigger specific metabolic adaptations that allow the pathogen to adhere to and penetrate the host tissue, scavenge nutrients, and overcome the host defense mechanisms. This metabolic shift and the interplay between metabolism, morphogenesis and stress response are important factors that have been extensively studied in several pathogens. Host cells also respond to the pathogen stimuli by activating intracellular signaling pathways that trigger the immune response against the infectious agent. The comprehension of the molecular aspects of these responses may help to establish new therapeutical strategies. In this review, different aspects of the biology of dermatophytes are addressed, with emphasis on the dermatophyte-host interaction and the mechanisms of antifungal resistance. Keywords: Antifungal agents; Dermatomycoses; Drug resistance, fungal; Host-pathogen interactions Resumo: As micoses cutâneas estão entre as infecções mais comuns em humanos e se tornaram um importante problema de saúde pública, principalmente por causarem infecções invasivas em pacientes imunodeprimidos. Durante a infecção, a interação dermatófito-hospedeiro desencadeia adaptações metabólicas específicas que permitem aos patógenos aderirem e penetrarem no tecido, remodelando seu metabolismo para captar nutrientes e superar os mecanismos de defesa do hospedeiro. Esse remodelamento metabólico e a inter-relação entre metabolismo, morfogênese e resposta ao estresse são importantes fatores que estão sendo intensamente avaliados em diversos patógenos. As células do hospedeiro também respondem aos estímulos do patógeno, ativando vias de sinalização intracelular que culminam no desencadeamento de uma resposta imune contra o agente infeccioso. O entendimento molecular dessas respostas metabólicas pode ajudar no estabelecimento de novas estratégias terapêuti-cas. Nesta revisão, são abordados diferentes aspectos da biologia dos dermatófitos, com ênfase na interação dermatófito-hospedeiro e nos mecanismos de resistência a antifúngicos.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Martins

Franceschini

Jacob

et al. 2016

Journal of Medical Microbiology

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Genomic sequencing of several dermatophyte species has revealed that they show small differences in genetic content and genome organization, although each fungus has adapted to specific niches. Thus, it seemed relevant to compare gene expression between species. Here, we examined the transcription modulation of three ATP-binding cassette (ABC) transporter genes (pdr1, mdr2 and mdr4), which code for membrane transporter proteins in four species of Trichophyton; T. interdigitale, T. rubrum, T. tonsurans and T. equinum. These fungal species were challenged with sub-lethal doses of griseofulvin, itraconazole, terbinafine and amphotericin B. A mutant strain of T. interdigitale, Dmdr2, was also analysed for the modulation of pdr1 and mdr4 genes to evaluate the possible functional interaction among these three genes. Disruption of the mdr2 gene resulted in the accumulation of high levels of mdr4 transcripts when challenged with griseofulvin, suggesting that the mdr4 gene is compensating for the inactivation of mdr2 by providing resistance to this antifungal. Although the three ABC transporter genes have high homology between the four dermatophytes analysed, it is likely that they have specific functions, suggesting that the action of each drug is dependent on other factors inherent to each species. Our data suggest that these ABC transporter genes act synergistically in dermatophytes, and they may compensate for one another when challenged with antifungal drugs. This may be an important cause of therapeutic failure when treating fungal infections.

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Isolation of transcripts over-expressed in human pathogen Trichophyton rubrum during growth in keratin

Cited by 65 publications

References 35 publications

Gene Expression Profiling in the Human Pathogenic Dermatophyte Trichophyton rubrum during Growth on Proteins

Gene Expression Profiling in the Human Pathogenic Dermatophyte Trichophyton rubrum during Growth on Proteins

Dermatófitos: interação patógeno-hospedeiro e resistência a antifúngicos

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

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