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RNA-sequencing analysis of Trichophyton rubrum transcriptome in response to sublethal doses of acriflavine.

ABSTRACT: BACKGROUND: The dermatophyte Trichophyton rubrum is an anthropophilic filamentous fungus that infects keratinized tissues and is the most common etiologic agent isolated in human dermatophytoses. The clinical treatment of these infections is challenging because only few antifungal drugs are commercially available. To understand the mode of action of cytotoxic drugs against fungi, we evaluated the time-dependent effects of acriflavine on T. rubrum transcriptome using high-throughput RNA-sequencing (RNA-seq) technology. RESULTS: RNA-seq analysis generated approximately 200 million short reads that were mapped to the Broad Institute's Dermatophyte Comparative Database before differential gene expression analysis was performed. By employing a stringent cut-off threshold of -1.5 and 1.5 log?-fold changes in gene expression, a subset of 490 unique genes were found to be modulated in T. rubrum in response to acriflavine exposure. Among the selected genes, 69 genes were modulated at all exposure time points. Functional categorization indicated the putative involvement of these genes in various cellular processes such as oxidation-reduction reaction, transmembrane transport, and metal ion binding. Interestingly, genes putatively involved in the pathogenicity of dermatophytoses were down-regulated suggesting that this drug interferes with the virulence of T. rubrum. Moreover, we identified 159 novel putative transcripts in intergenic regions and two transcripts in intron regions of T. rubrum genome. CONCLUSION: The results provide insights into the molecular events underlying the stress responses of T. rubrum to acriflavine, revealing that this drug interfered with important molecular events involved in the establishment and maintenance of fungal infection in the host. In addition, the identification of novel transcripts will further enable the improvement of gene annotation and open reading frame prediction of T. rubrum and other dermatophyte genomes.

SUBMITTER: Persinoti GF

PROVIDER: S-EPMC4243288 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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RNA-sequencing analysis of Trichophyton rubrum transcriptome in response to sublethal doses of acriflavine.

Persinoti Gabriela Felix GF de Aguiar Peres Nalu Teixeira NT Jacob Tiago Rinaldi TR Rossi Antonio A Vêncio Ricardo Zorzetto RZ Martinez-Rossi Nilce Maria NM

BMC genomics 20141027

<h4>Background</h4>The dermatophyte Trichophyton rubrum is an anthropophilic filamentous fungus that infects keratinized tissues and is the most common etiologic agent isolated in human dermatophytoses. The clinical treatment of these infections is challenging because only few antifungal drugs are commercially available. To understand the mode of action of cytotoxic drugs against fungi, we evaluated the time-dependent effects of acriflavine on T. rubrum transcriptome using high-throughput RNA-se ...[more]

PMID: 25573029

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Project description:Although most mycoses are superficial, the dermatophyte Trichophyton rubrum can cause systemic infections in patients with a weakened immune system, resulting in serious and deep lesions. The aim of this study was to analyze the transcriptome of a human monocyte/macrophage cell line (THP-1) co-cultured with inactivated germinated T. rubrum conidia (IGC) in order to characterize deep infection. Analysis of macrophage viability by lactate dehydrogenase quantification showed the activation of the immune system after 24 h of contact with live germinated T. rubrum conidia (LGC). After standardization of the co-culture conditions, the release of the interleukins TNF-α, IL-8, and IL-12 was quantified. The greater release of IL-12 was observed during co-culturing of THP-1 with IGC, while there was no change in the other cytokines. Next-generation sequencing of the response to T. rubrum IGC identified the modulation of 83 genes; of these, 65 were induced and 18 were repressed. The categorization of the modulated genes showed their involvement in signal transduction, cell communication, and immune response pathways. In total, 16 genes were selected for validation and Pearson's correlation coefficient was 0.98, indicating a high correlation between RNA-seq and qPCR. Modulation of the expression of all genes was similar for LGC and IGC co-culture; however, the fold-change values were higher for LGC. Due to the high expression of the IL-32 gene in RNA-seq, we quantified this interleukin and observed an increased release in co-culture with T. rubrum. In conclusion, the macrophages-T. rubrum co-culture model revealed the ability of these cells to modulate the immune response, as demonstrated by the release of proinflammatory cytokines and the RNA-seq gene expression profile. The results obtained permit to identify possible molecular targets that are modulated in macrophages and that could be explored in antifungal therapies involving the activation of the immune system.

Dataset Information

RNA-sequencing analysis of Trichophyton rubrum transcriptome in response to sublethal doses of acriflavine.

Publications

RNA-sequencing analysis of Trichophyton rubrum transcriptome in response to sublethal doses of acriflavine.

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