P. brasiliensis Virulence Is Affected by SconC, the Negative Regulator of Inorganic Sulfur Assimilation

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.

Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant

“…This mutant is completely virulent, which excludes inorganic S compounds (except H 2 S) and taurine as being required S sources in vivo. This result correlates with previously reported information on the pathogenic fungus Paracoccidioides brasiliensis: this fungus also penetrates the human body through the respiratory tract to infect lung alveoli, and it is known that the yeast form, the parasitic morphotype, cannot assimilate inorganic S sources (86)(87)(88) and, thus, must feed on organic S compounds. Interestingly, the sF⌬ strain was furthermore unable to grow on BSA as a source of sulfur and/or nitrogen.…”

New insights into a complex fungal pathogen: the case of Paracoccidioides spp.

“…Moreover, the 14–3–3 protein and Gp43 induce apoptosis in human pneumocytes (Silva et al ., ). The second virulence mechanism is the conidia/mycelium‐to‐yeast transition, a morphological process due not only to the temperature shift to 37 °C but also to the availability of organic sulphur compounds (Menino et al ., ). A negative regulator of the inorganic sulphur assimilation pathway has also been described.…”

“…This molecule (SconCp) is considered to be a novel virulence determinant in P . brasiliensis (Menino et al ., ).…”

Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens: what is known and why do we need to know more?

“…Cellular levels of cysteine and methionine reflect intracellular sulphur content and modulate sulphur uptake via sulphur metabolite repression involving the positive-acting Cys3/MetR transcription factor and the negative-acting Scon proteins. Recently these regulators have been found to be important for fungal pathogenicity [6][7][8] (and references therein).…”