Evaluation of the role of dimorphism regulatory histidine kinase (Drk1) in cell wall modulation and pathogenicity of Paracoccidioides brasiliensis

Abstract

Dimorphic and thermo-dependent fungi of the genus Paracoccidioides spp. are causative agents of Paracoccidioidomycosis (PCM), a systemic mycosis endemic in Latin America. PCM has a high prevalence in Brazil, affecting mainly rural workers. In the soil (22-25°C), these fungi grow as septate hyphae. When inhaled into the warm lungs of a mammalian host (37°C), these infectious propagules convert into pathogenic yeast. This ability to make the transition between mycelium and yeast is essential for the establishment and spread of the disease. It is known that different genes are expressed according to the stage of the fungus, and in recent years genes related to the control of the mycelium-yeast transition (M-Y) have been identified. In dimorphic fungi species, the regulation of a dimorphism regulating histidine kinase (DRK1) is expressed mainly in the yeast phase. Recently, our group characterized the expression of this gene in P. brasiliensis, and we demonstrated its role in dimorphism, using a specific inhibitor of this histidine kinase (iprodione - iDrk). We observed that the fungus treated with iDrk remained in the mycelial form even when cultivated at 37°C. In addition, yeast cells cultivated in high salt concentration showed increase of PbDRK1 expression, indicating a relationship with the Hog1 MAP kinase pathway in P. brasiliensis. Thus, histidines kinases have an important role in regulating cell virulence and survival, and the investigation of signal transduction pathways associated with these kinases can assist in the discovery of potential new pharmacological targets and consequently the development of drugs with antifungal activity, once that histidines kinases are present in prokaryotes, plants, bacteria and fungi but absent in mammalian cells. Thus, this study will aim to evaluate the role of PbDrk1 in the pathogenicity of the fungus, as well as the potential signaling pathway involved. Finnaly, the characterization of PbDrk1 and its signaling pathway will serve to better understand the mechanisms involved with the dimorphic transition, fungal virulence and probably in the development of PCM. (AU)