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The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall.

ABSTRACT: Dimorphic fungi of the Paracoccidioides genus are the causative agents of paracoccidioidomycosis (PCM), an endemic disease in Latin America with a high incidence in Brazil. This pathogen presents as infective mycelium at 25 °C in the soil, reverting to its pathogenic form when inhaled by the mammalian host (37 °C). Among these dimorphic fungal species, dimorphism regulating histidine kinase (Drk1) plays an essential role in the morphological transition. These kinases are present in bacteria and fungi but absent in mammalian cells and are important virulence and cellular survival regulators. Hence, the purpose of this study was to investigate the role of PbDrk1 in the cell wall modulation of P. brasiliensis. We observed that PbDrk1 participates in fungal resistance to different cell wall-disturbing agents by reducing viability after treatment with iDrk1. To verify the role of PbDRK1 in cell wall morphogenesis, qPCR results showed that samples previously exposed to iDrk1 presented higher expression levels of several genes related to cell wall modulation. One of them was FKS1, a β-glucan synthase that showed a 3.6-fold increase. Furthermore, confocal microscopy analysis and flow cytometry showed higher β-glucan exposure on the cell surface of P. brasiliensis after incubation with iDrk1. Accordingly, through phagocytosis assays, a significantly higher phagocytic index was observed in yeasts treated with iDrk1 than the control group, demonstrating the role of PbDrk1 in cell wall modulation, which then becomes a relevant target to be investigated. In parallel, the immune response profile showed increased levels of proinflammatory cytokines. Finally, our data strongly suggest that PbDrk1 modulates cell wall component expression, among which we can identify β-glucan. Understanding this signalling pathway may be of great value for identifying targets of antifungal molecular activity since HKs are not present in mammals.

SUBMITTER: Navarro MV

PROVIDER: S-EPMC8707131 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTranscriptome sequences provide a complement to structural genomic information and provide snapshots of an organism's transcriptional profile. Such sequences also represent an alternative method for characterizing neglected species that are not expected to undergo whole-genome sequencing. One difficulty for transcriptome sequencing of these organisms is the low quality of reads and incomplete coverage of transcripts, both of which compromise further bioinformatics analyses. Another complicating factor is the lack of known protein homologs, which frustrates searches against established protein databases. This lack of homologs may be caused by divergence from well-characterized and over-represented model organisms. Another explanation is that non-coding RNAs (ncRNAs) may be caught during sequencing. NcRNAs are RNA sequences that, unlike messenger RNAs, do not code for protein products and instead perform unique functions by folding into higher order structural conformations. There is ncRNA screening software available that is specific for transcriptome sequences, but their analyses are optimized for those transcriptomes that are well represented in protein databases, and also assume that input ESTs are full-length and high quality.ResultsWe propose an algorithm called PORTRAIT, which is suitable for ncRNA analysis of transcriptomes from poorly characterized species. Sequences are translated by software that is resistant to sequencing errors, and the predicted putative proteins, along with their source transcripts, are evaluated for coding potential by a support vector machine (SVM). Either of two SVM models may be employed: if a putative protein is found, a protein-dependent SVM model is used; if it is not found, a protein-independent SVM model is used instead. Only ab initio features are extracted, so that no homology information is needed. We illustrate the use of PORTRAIT by predicting ncRNAs from the transcriptome of the pathogenic fungus Paracoccidoides brasiliensis and five other related fungi.ConclusionPORTRAIT can be integrated into pipelines, and provides a low computational cost solution for ncRNA detection in transcriptome sequencing projects.

Dataset Information

The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall.

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