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Global modulation of gene expression in Paracoccidioides brasiliensis in response to thioridazine

ABSTRACT: Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which have been shown to present antimicrobial activity (in vitro and in vivo) against a great variety of pathogenic microorganisms, including bacteria, parasites (protozoa and helmints) and fungi. In this study, we used competitive microarray hybridization to evaluate the effects of increasing concentrations of the piperidinic phenothiazine derivative thioridazine (TR) on the transcriptome of Paracoccidioides brasiliensis, the causative agent of paracoccidioidomycosis (PCM) - the most common systemic mycosis in Latin America. These analyses showed that the presence of TR affected expression of more than 1,800 genes from this fungus, including genes related to cellular processes such as cell wall metabolism and drug resistance.

ORGANISM(S): Paracoccidioides brasiliensis

PROVIDER: GSE41881 | GEO | 2013/12/31

SECONDARY ACCESSION(S): PRJNA178604

REPOSITORIES: GEO

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Project description:Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which have been shown to present antimicrobial activity (in vitro and in vivo) against a great variety of pathogenic microorganisms, including bacteria, parasites (protozoa and helmints) and fungi. In this study, we used competitive microarray hybridization to evaluate the effects of increasing concentrations of the piperidinic phenothiazine derivative thioridazine (TR) on the transcriptome of Paracoccidioides brasiliensis, the causative agent of paracoccidioidomycosis (PCM) - the most common systemic mycosis in Latin America. These analyses showed that the presence of TR affected expression of more than 1,800 genes from this fungus, including genes related to cellular processes such as cell wall metabolism and drug resistance. Microarray hybridizations were carried out with amplified RNA (aRNA), which was produced starting with total RNA extracted from cells treated with thioridazine (15, 20 or 25 M-BM-5M) for 168 hours. The aRNA synthesized from cells unexposed to TR was taken as reference. Each treatment was analyzed with two independent hybridizations (a pair of hybridizations, with dye-swaps within each pair). Since each biochip carried two replicas of the arrayed genes, a total of four intensity readings were generated for each element in the microarray.The data has been filtered, normalized and adjusted as described in the "data processing" box for each individual sample. Dye swap consistency checking has been performed between equivalent experimental pairs with the aid of the software TIGR MIDAS v2.19 and inconsistent spots have been flagged and excluded from further analyses. The values obtained from each dye swap pair have been averaged and consolidated into a single data file, generating a total of 8 hybridization files (four from each treatment concentration). These files have been loaded into the software TIGR Multi-Experiment Viewer, v.3.1 Experiments were then normalized and genes that displayed statistically significant modulation were identified by one-way ANOVA, considering p < 0.01 as a cutoff value. A list of statisticaly significant, modulated genes was created, showing the average log ratio for each one of these genes, within each time point.

Project description:Paracoccidioidomycosis (PCM) is an endemic mycosis in Latin America. The PCM is a systemic disease caused by the thermo dimorphic fungus Paracoccidioides spp, which can exist as mycelia and yeast forms. The mycelia form can be found in environment at temperatures between 18 °C and 25 °C and produces spores or conidia. The PCM infection route occurs by the inhalation of conidia. Once in the lungs, these particles are converted into yeasts pathogenic form. Until now, metabolic aspects and virulence factors related to Paracoccidioides lutzii infective propagule are little understood. In this concern, a global proteomic study of P. lutzii conidia was performed. For conidia production, the mycelia of the isolate Pb01 were cultured in potato agar medium during 90 days at 18 °C. Obtained conidia were collected and purified. The proteins were extracted and subjected to tryptic digestion followed by identification by NanoUPLC-MSE approach. We identified a total of 242 proteins in P. lutzii conidia which were subjected to in silico functional analysis Proteins putatively acting as adhesins, such as GAPDH, enolase, and the glycoprotein β-1,3-glucanosyltransferase (gel2) were identified during our analysis. We also identified proteins related to signal transduction pathways, such as Ras and RhoA GTPases, previously demonstrated to be required for morphologic changes in pathogenic fungi. Proteins related to evasion, defense and virulence were also identified. Proteins acting during temperature shifts or oxidative stress provided by the host environment such as HSP90, catalase, mitochondrial peroxiredoxin Prx1 were identified. It were also identified proteins related to energy production and protein biosynthesis, which can provide important aspects to survival of this resting cells. These results highlight that P. lutzii conidia contain proteins that can contribute to its maintenance in the environment and also molecules related to host-pathogen interactions.

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Global modulation of gene expression in Paracoccidioides brasiliensis in response to thioridazine

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