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

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dc.contributorVirginia Techen
dc.contributor.authorWillger, Sven D.en
dc.contributor.authorPuttikamonkul, Srisombaten
dc.contributor.authorKim, Kwang-Hyungen
dc.contributor.authorBurritt, James B.en
dc.contributor.authorGrahl, Noraen
dc.contributor.authorMetzler, Laurel J.en
dc.contributor.authorBarbuch, Roberten
dc.contributor.authorBard, Martinen
dc.contributor.authorLawrence, Christopher B.en
dc.contributor.authorCramer, Robert A. Jr.en
dc.date.accessed2014-05-14en
dc.date.accessioned2014-06-17T20:12:09Zen
dc.date.available2014-06-17T20:12:09Zen
dc.date.issued2008-11-07en
dc.description.abstractAt 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.en
dc.description.sponsorshipRAC is currently supported by funding from the National Institutes of Health, COBRE grant RR020185, and the Montana State University Agricultural Experiment Station. M.B. acknowledges the support of NIH grant GM62104.en
dc.identifier.citationWillger SD, Puttikamonkul S, Kim K-H, Burritt JB, Grahl N, et al. (2008) A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus. PLoS Pathog 4(11): e1000200. doi:10.1371/journal.ppat.1000200en
dc.identifier.doihttps://doi.org/10.1371/journal.ppat.1000200en
dc.identifier.issn1553-7374en
dc.identifier.urihttp://hdl.handle.net/10919/49007en
dc.identifier.urlhttp://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000200en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectAspergillus fumigatusen
dc.subjectBiosynthesisen
dc.subjectFungal pathogensen
dc.subjectFungien
dc.subjectGene regulationen
dc.subjectHypoxiaen
dc.subjectMedical hypoxiaen
dc.subjectSterolsen
dc.titleA Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatusen
dc.title.serialPLoS Pathogensen
dc.typeArticle - Refereeden

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