title: Identification of hypoxia-inducible target genes of Aspergillus fumigatus by transcriptome analysis reveals cellular respiration as an important contributor to hypoxic survival.
abstract: Aspergillus fumigatus is an opportunistic, airborne pathogen that causes invasive aspergillosis in immunocompromised patients. During the infection process, A. fumigatus is challenged by hypoxic microenvironments occurring in inflammatory, necrotic tissue. To gain further insights into the adaptation mechanism, A. fumigatus was cultivated in an oxygen-controlled chemostat under hypoxic and normoxic conditions. Transcriptome analysis revealed a significant increase in transcripts associated with cell wall polysaccharide metabolism, amino acid and metal ion transport, nitrogen metabolism, and glycolysis. A concomitant reduction in transcript levels was observed with cellular trafficking and G-protein-coupled signaling. To learn more about the functional roles of hypoxia-induced transcripts, we deleted A. fumigatus genes putatively involved in reactive nitrogen species detoxification (fhpA), NAD(+) regeneration (frdA and osmA), nitrogen metabolism (niaD and niiA), and respiration (rcfB). We show that the nitric oxygen (NO)-detoxifying flavohemoprotein gene fhpA is strongly induced by hypoxia independent of the nitrogen source but is dispensable for hypoxic survival. By deleting the nitrate reductase gene niaD, the nitrite reductase gene niiA, and the two fumarate reductase genes frdA and osmA, we found that alternative electron acceptors, such as nitrate and fumarate, do not have a significant impact on growth of A. fumigatus during hypoxia, but functional mitochondrial respiratory chain complexes are essential under these conditions. Inhibition studies indicated that primarily complexes III and IV play a crucial role in the hypoxic growth of A. fumigatus.
authors.affiliation: Department of Molecular and Applied Microbiology, the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Kroll
authors.affiliation: Department of Molecular and Applied Microbiology, the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany Integrated Research Treatment-Center, Center for Sepsis Control and Care (CSCC), University Hospital Jena, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Pähtz
authors.affiliation: Department of Molecular and Applied Microbiology, the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Hillmann
authors.affiliation: Department of Clinical Microbiology and Immunology, Aspergillus and Antifungal Research Laboratory, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel.
authors.forename: Yakir
authors.initials: Y
authors.lastname: Vaknin
authors.affiliation: Research Group Systems Biology/Bioinformatics, the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schmidt-Heck
authors.affiliation: Bio Pilot Plant, the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Roth
authors.affiliation: Research Group Microbial Immunology, the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany.
authors.forename: Ilse D
authors.initials: ID
authors.lastname: Jacobsen
authors.affiliation: Department of Clinical Microbiology and Immunology, Aspergillus and Antifungal Research Laboratory, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Osherov
authors.affiliation: Department of Molecular and Applied Microbiology, the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Axel A
authors.initials: AA
authors.lastname: Brakhage
authors.affiliation: Department of Molecular and Applied Microbiology, the Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Jena, Germany Integrated Research Treatment-Center, Center for Sepsis Control and Care (CSCC), University Hospital Jena, Germany olaf.kniemeyer@hki-jena.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Kniemeyer
mesh_terms: D001228:Aspergillosis / Q000235:genetics* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D015687:Cell Hypoxia / Q000235:genetics*; D019069:Cell Respiration / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D005656:Fungal Proteins / Q000096:biosynthesis; D020869:Gene Expression Profiling; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D010100:Oxygen / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D010100:Oxygen
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