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.
Highlights
Aspergillus fumigatus is a normally benign saprophytic fungus that may cause an often lethal invasive disease in immunocompromised patients, invasive pulmonary aspergillosis (IPA) [1,2]
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
Summary
Aspergillus fumigatus is a normally benign saprophytic fungus that may cause an often lethal invasive disease in immunocompromised patients, invasive pulmonary aspergillosis (IPA) [1,2]. While IPA can be caused by several Aspergillus species, the majority of IPA cases are caused by A. fumigatus. This may suggest that A. fumigatus contains unique attributes that allow it to cause disease [3]. The mechanisms utilized by A. fumigatus to survive and cause disease in immunocompromised hosts are not fully understood [4]. Infection generates significant inflammation and necrosis in lung tissue that can be visualized by histopathology. These pathologic lesions likely represent areas of poor oxygen availability to the pathogen and host
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