title: Divergent targets of Aspergillus fumigatus AcuK and AcuM transcription factors during growth in vitro versus invasive disease.
abstract: In Aspergillus nidulans, the AcuK and AcuM transcription factors form a complex that regulates gluconeogenesis. In Aspergillus fumigatus, AcuM governs gluconeogenesis and iron acquisition in vitro and virulence in immunosuppressed mice. However, the function of AcuK was previously unknown. Through in vitro studies, we found that A. fumigatus ΔacuK single and ΔacuK ΔacuM double mutants had impaired gluconeogenesis and iron acquisition, similar to the ΔacuM mutant. Also, the ΔacuK, ΔacuM, and ΔacuK ΔacuM mutants had similar virulence defects in mice. However, the ΔacuK mutant had a milder defect in extracellular siderophore activity and induction of epithelial cell damage in vitro than did the ΔacuM mutant. Moreover, overexpression of acuM in the ΔacuK mutant altered expression of 3 genes and partially restored growth under iron-limited conditions, suggesting that AcuM can govern some genes independently of AcuK. Although the ΔacuK and ΔacuM mutants had very similar transcriptional profiles in vitro, their transcriptional profiles during murine pulmonary infection differed both from their in vitro profiles and from each other. While AcuK and AcuM governed the expression of only a few iron-responsive genes in vivo, they influenced the expression of other virulence-related genes, such as hexA and dvrA. Therefore, in A. fumigatus, while AcuK and AcuM likely function as part of the same complex, they can also function independently of each other. Furthermore, AcuK and AcuM have different target genes in vivo than in vitro, suggesting that in vivo infection stimulates unique transcriptional regulatory pathways in A. fumigatus.
authors.affiliation: Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Monsicha
authors.initials: M
authors.lastname: Pongpom
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Microbiology and Immunology and Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Snarr
authors.affiliation: Department of Microbiology and Immunology and Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Sheppard
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Mitchell
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA David Geffen School of Medicine at UCLA, Los Angeles, California, USA sfiller@ucla.edu.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Filler
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000235:genetics* / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D003348:Cortisone / Q000008:administration & dosage / Q000031:analogs & derivatives; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D005943:Gluconeogenesis / Q000235:genetics; D016867:Immunocompromised Host; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017262:Siderophores / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D017262:Siderophores; D014157:Transcription Factors; D007501:Iron; D003348:Cortisone