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Background  Hypoxic microenvironments are generated during fungal infection. It has been described that to survive in the human host, fungi must also tolerate and overcome  in vivo  microenvironmental stress conditions including low oxygen tension; however nothing is known how  Paracoccidioides  species respond to hypoxia. The genus  Paracoccidioides  comprises human thermal dimorphic fungi and are causative agents of paracoccidioidomycosis (PCM), an important mycosis in Latin America.    Methodology/Principal Findings  In this work, a detailed hypoxia characterization was performed in  Paracoccidioides . Using NanoUPLC-MS E  proteomic approach, we obtained a total of 288 proteins differentially regulated in 12 and 24 h of hypoxia, providing a global view of metabolic changes during this stress. In addition, a functional characterization of the homologue to the most important molecule involved in hypoxia responses in other fungi, the SREBP (sterol regulatory element binding protein) was performed. We observed that  Paracoccidioides  species have a functional homologue of SREBP, named here as SrbA, detected by using a heterologous genetic approach in the  srbA  null mutant in  Aspergillus fumigatus .  Paracoccidioides srbA  ( PbsrbA ), in addition to involvement in hypoxia, is probable involved in iron adaptation and azole drug resistance responses.    Conclusions/Significance  In this study, the hypoxia was characterized in  Paracoccidioides . The first results can be important for a better understanding of the fungal adaptation to the host and improve the arsenal of molecules for the development of alternative treatment options in future, since molecules related to fungal adaptation to low oxygen levels are important to virulence and pathogenesis in human pathogenic fungi.

Characterization of the Paracoccidioides Hypoxia Response Reveals New Insights into Pathogenesis Mechanisms of This Important Human Pathogenic Fungus