title: Iron acquisition and oxidative stress response in aspergillus fumigatus.
abstract: BACKGROUND
  Aspergillus fumigatus is a ubiquitous airborne fungal pathogen that presents a life-threatening health risk to individuals with weakened immune systems. A. fumigatus pathogenicity depends on its ability to acquire iron from the host and to resist host-generated oxidative stress. Gaining a deeper understanding of the molecular mechanisms governing A. fumigatus iron acquisition and oxidative stress response may ultimately help to improve the diagnosis and treatment of invasive aspergillus infections.
  
  
  RESULTS
  This study follows a systems biology approach to investigate how adaptive behaviors emerge from molecular interactions underlying A. fumigatus iron regulation and oxidative stress response. We construct a Boolean network model from known interactions and simulate how changes in environmental iron and superoxide levels affect network dynamics. We propose rules for linking long term model behavior to qualitative estimates of cell growth and cell death. These rules are used to predict phenotypes of gene deletion strains. The model is validated on the basis of its ability to reproduce literature data not used in model generation.
  
  
  CONCLUSIONS
  The model reproduces gene expression patterns in experimental time course data when A. fumigatus is switched from a low iron to a high iron environment. In addition, the model is able to accurately represent the phenotypes of many knockout strains under varying iron and superoxide conditions. Model simulations support the hypothesis that intracellular iron regulates A. fumigatus transcription factors, SreA and HapX, by a post-translational, rather than transcriptional, mechanism. Finally, the model predicts that blocking siderophore-mediated iron uptake reduces resistance to oxidative stress. This indicates that combined targeting of siderophore-mediated iron uptake and the oxidative stress response network may act synergistically to increase fungal cell killing.
authors.affiliation: Center for Cell Analysis and Modeling, University of Connecticut Health Center, 400 Farmington Ave, Farmington, 06030, USA. mbrandon@uchc.edu.|Center for Quantitative Medicine, University of Connecticut Health Center, Farmington, 06030, USA. mbrandon@uchc.edu.
authors.forename: Madison
authors.initials: M
authors.lastname: Brandon
authors.affiliation: Department of Biological Sciences, Virginia Tech, 1405 Perry Street, Blacksburg, 24061, USA. bahoward@vbi.vt.edu.|Virginia Bioinformatics Institute, Virginia Tech, 1015 Life Science Circle, Blacksburg, 24061, US. bahoward@vbi.vt.edu.
authors.forename: Brad
authors.initials: B
authors.lastname: Howard
authors.affiliation: Department of Biological Sciences, Virginia Tech, 1405 Perry Street, Blacksburg, 24061, USA. lawrence@vbi.vt.edu.|Virginia Bioinformatics Institute, Virginia Tech, 1015 Life Science Circle, Blacksburg, 24061, US. lawrence@vbi.vt.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lawrence
authors.affiliation: Center for Quantitative Medicine, University of Connecticut Health Center, Farmington, 06030, USA. laubenbacher@uchc.edu.|The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, 06030, USA. laubenbacher@uchc.edu.|Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, 06030, USA. laubenbacher@uchc.edu.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Laubenbacher
mesh_terms: D001232:Aspergillus fumigatus / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D016923:Cell Death; D049109:Cell Proliferation; D004777:Environment; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D017262:Siderophores / Q000096:biosynthesis; D013269:Stochastic Processes; D013481:Superoxides / Q000378:metabolism; D049490:Systems Biology
chemical_list: D005656:Fungal Proteins; D017262:Siderophores; D013481:Superoxides; D007501:Iron; D010100:Oxygen