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

Date Published: December 10, 2015

Publisher: Public Library of Science

Author(s): Patrícia de Sousa Lima, Dawoon Chung, Alexandre Melo Bailão, Robert A. Cramer, Célia Maria de Almeida Soares, Joseph M. Vinetz.

Abstract: BackgroundHypoxic 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 FindingsIn this work, a detailed hypoxia characterization was performed in Paracoccidioides. Using NanoUPLC-MSE 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/SignificanceIn 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.

Partial Text: The genus Paracoccidioides is a complex of thermodimorphic fungi, and are causative agents of paracoccidioidomycosis (PCM) a deep systemic granulomatous mycosis, endemic in Latin America [1, 2]. Paracoccidioides spp. grows as yeast in host tissue and in vitro at 36°C, and as mycelium under saprobiotic and laboratory conditions (18–23°C). As the dimorphism is dependent on temperature, when the mycelia or conidia are inhaled into the host respiratory tract, the transition to the pathogenic yeast phase occurs [3]. Once in the lungs, epithelial cells and resident macrophages are the first line of defence against Paracoccidioides cells. Inside macrophages, the parasitic yeast form subverts the normally harsh intraphagosomal environment and proliferates [4]. Adhesion to and invasion of epithelial cells and basal lamina proteins may be required for the extra pulmonary haematogenous fungal dissemination to organs and tissues [1, 3, 5].



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