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.
Highlights
Paracoccidioidomycosis (PCM) is a systemic granulomatous human disease endemic in Latin America. It is caused by Paracoccidioides spp., a thermally-dimorphic fungus that presents as an infective mycelium in the environment, and it switches to a pathogenic yeast form in the mammalian host [1,2]
The recognition of fungal cell wall components begins with pathogen-associated molecular patterns (PAMPs) through pathogen recognition receptors (PRRs)
Since Histidine kinases (HKs) are known to regulate morphological switches in P. brasiliensis, this work aimed to characterize the PbDrk1 protein, which is involved in the transition from mycelium to yeast
Summary
Paracoccidioidomycosis (PCM) is a systemic granulomatous human disease endemic in Latin America. It is caused by Paracoccidioides spp., a thermally-dimorphic fungus that presents as an infective mycelium in the environment, and it switches to a pathogenic yeast form in the mammalian host [1,2]. The recognition of fungal cell wall components begins with pathogen-associated molecular patterns (PAMPs) through pathogen recognition receptors (PRRs). These receptors include Toll-like receptors (TLRs), mannose receptors, complement pathway molecules and lectin family receptors (CLRs), such as dectin-1 [8]. The interaction of these molecules with fungal yeasts leads to activation of the innate immune response, activating mediators involved in eliminating these pathogens and controlling the adaptive immune response [9]
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