Abstract
Conidia/mycelium-to-yeast transition of Paracoccidioides brasiliensis is a critical step for the establishment of paracoccidioidomycosis, a systemic mycosis endemic in Latin America. Thus, knowledge of the factors that mediate this transition is of major importance for the design of intervention strategies. So far, the only known pre-requisites for the accomplishment of the morphological transition are the temperature shift to 37°C and the availability of organic sulfur compounds. In this study, we investigated the auxotrophic nature to organic sulfur of the yeast phase of Paracoccidioides , with special attention to P. brasiliensis species. For this, we addressed the role of SconCp, the negative regulator of the inorganic sulfur assimilation pathway, in the dimorphism and virulence of this pathogen. We show that down-regulation of SCONC allows initial steps of mycelium-to-yeast transition in the absence of organic sulfur compounds, contrarily to the wild-type fungus that cannot undergo mycelium-to-yeast transition under such conditions. However, SCONC down-regulated transformants were unable to sustain yeast growth using inorganic sulfur compounds only. Moreover, pulses with inorganic sulfur in SCONC down-regulated transformants triggered an increase of the inorganic sulfur metabolism, which culminated in a drastic reduction of the ATP and NADPH cellular levels and in higher oxidative stress. Importantly, the down-regulation of SCONC resulted in a decreased virulence of P. brasiliensis, as validated in an in vivo model of infection. Overall, our findings shed light on the inability of P. brasiliensis yeast to rely on inorganic sulfur compounds, correlating its metabolism with cellular energy and redox imbalances. Furthermore, the data herein presented reveal SconCp as a novel virulence determinant of P. brasiliensis.
Highlights
Paracoccidioides brasiliensis is a dimorphic fungus and a causative agent of paracoccidioidomycosis, an endemic mycosis affecting the population from Latin America countries such as Brazil, Colombia and Venezuela [1]
Up-regulated in the AsSCONC transformants was the expression of several downstream genes of the inorganic sulfur assimilatory pathway (Figure 2.CE) and that of choline sulfatase (CHS) (Figure 2.F), an enzyme of the lateral branch of the inorganic sulfur assimilation pathway, that uses as substrate choline-O-sulfate, a osmoprotectant and an additional intracellular source of inorganic sulfur [18]
The understanding of the mechanisms underlying the morphological transition of P. brasiliensis from the conidia/ mycelial phase to the pathogenic yeast phase is essential, as this is critical for the establishment and development of paracoccidioidomycosis
Summary
Paracoccidioides brasiliensis is a dimorphic fungus and a causative agent of paracoccidioidomycosis, an endemic mycosis affecting the population from Latin America countries such as Brazil, Colombia and Venezuela [1]. It is likely that this change plays a role in the fungus pathogenesis For these reasons, a better understanding of the impact played by SconCp on the sulfur-dependent dimorphic processes in P. brasiliensis is crucial, as it may highlight a new P. brasiliensis virulence factor. A better understanding of the impact played by SconCp on the sulfur-dependent dimorphic processes in P. brasiliensis is crucial, as it may highlight a new P. brasiliensis virulence factor To address these questions, we down-regulated the expression of SCONC in isolates from different Paracoccidioides species and investigated its impact both on the inorganic sulfur assimilatory pathway and on the dimorphic transition. We present evidence that P. brasiliensis SconCp acts as a regulator of dimorphism by modulating the inorganic sulfur metabolism, thereby influencing the virulence of this pathogenic fungus
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