title: Network Modeling Reveals Cross Talk of MAP Kinases during Adaptation to Caspofungin Stress in Aspergillus fumigatus.
abstract: Mitogen activated protein kinases (MAPKs) are highly conserved in eukaryotic organisms. In pathogenic fungi, their activities were assigned to different physiological functions including drug adaptation and resistance. Aspergillus fumigatus is a human pathogenic fungus, which causes life-threatening invasive infections. Therapeutic options against invasive mycoses are still limited. One of the clinically used drugs is caspofungin, which specifically targets the fungal cell wall biosynthesis. A systems biology approach, based on comprehensive transcriptome data sets and mathematical modeling, was employed to infer a regulatory network and identify key interactions during adaptation to caspofungin stress in A. fumigatus. Mathematical modeling and experimental validations confirmed an intimate cross talk occurring between the cell wall-integrity and the high osmolarity-glycerol signaling pathways. Specifically, increased concentrations of caspofungin promoted activation of these signalings. Moreover, caspofungin affected the intracellular transport, which caused an additional osmotic stress that is independent of glucan inhibition. High concentrations of caspofungin reduced this osmotic stress, and thus decreased its toxic activity. Our results demonstrated that MAPK signaling pathways play a key role during caspofungin adaptation and are contributing to the paradoxical effect exerted by this drug.
authors.affiliation: Department of Systems Biology/Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Altwasser
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany; Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Adolf-Reichwein-Str. 23, 07745, Jena, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Baldin
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany; Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Adolf-Reichwein-Str. 23, 07745, Jena, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Weber
authors.affiliation: Department of Systems Biology/Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Guthke
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany; Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Adolf-Reichwein-Str. 23, 07745, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07747, Jena, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Kniemeyer
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany; Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University Jena, Adolf-Reichwein-Str. 23, 07745, Jena, Germany.
authors.forename: Axel A
authors.initials: AA
authors.lastname: Brakhage
authors.affiliation: Department of Systems Biology/Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Linde
authors.affiliation: Leibniz Junior Research Group-Biobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany.
authors.forename: Vito
authors.initials: V
authors.lastname: Valiante
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D015153:Blotting, Western; D000077336:Caspofungin; D002463:Cell Membrane Permeability / Q000187:drug effects; D054714:Echinocandins / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects*; D005800:Genes, Fungal; D056726:Genetic Association Studies; D055666:Lipopeptides; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012984:Software; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*
chemical_list: D054714:Echinocandins; D055666:Lipopeptides; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D000077336:Caspofungin