A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus

Abstract

At the site of microbial infections, the significant influx of immune effector cells and the necrosis of tissue by the invading pathogen generate hypoxic microenvironments in which both the pathogen and host cells must survive. Currently, whether hypoxia adaptation is an important virulence attribute of opportunistic pathogenic molds is unknown. Here we report the characterization of a sterol-regulatory element binding protein, SrbA, in the opportunistic pathogenic mold, Aspergillus fumigatus. Loss of SrbA results in a mutant strain of the fungus that is incapable of growth in a hypoxic environment and consequently incapable of causing disease in two distinct murine models of invasive pulmonary aspergillosis (IPA). Transcriptional profiling revealed 87 genes that are affected by loss of SrbA function. Annotation of these genes implicated SrbA in maintaining sterol biosynthesis and hyphal morphology. Further examination of the SrbA null mutant consequently revealed that SrbA plays a critical role in ergosterol biosynthesis, resistance to the azole class of antifungal drugs, and in maintenance of cell polarity in A. fumigatus. Significantly, the SrbA null mutant was highly susceptible to fluconazole and voriconazole. Thus, these findings present a new function of SREBP proteins in filamentous fungi, and demonstrate for the first time that hypoxia adaptation is likely an important virulence attribute of pathogenic molds.

Author Summary

The incidence of potentially lethal infections caused by normally benign molds has increased tremendously over the last two decades. One disease in particular, invasive pulmonary aspergillosis (IPA), caused by the common mold Aspergillus fumigatus, has become the leading cause of death due to invasive mycoses. Currently, we have a limited understanding of how this opportunistic pathogen causes disease in immunocompromised patients. In this study, we discover a previously unexplored mechanism required by this mold to cause disease, hypoxia (low oxygen) adaptation. We report that hypoxia adaptation in A. fumigatus is mediated in part by a highly conserved transcription factor, SrbA, a protein in the sterol regulatory element binding protein family. A null mutant of SrbA was unable to grow in hypoxia, displayed increased susceptibility to the azole class of antifungal drugs, and was avirulent in two distinct murine models of IPA. Importantly, we report the discovery of a novel function of SrbA in molds related to maintenance of cell polarity. The finding that SrbA regulates resistance to the azole class of antifungal drugs presents an opportunity to uncover new mechanisms of antifungal drug resistance in A. fumigatus.