Network Modeling Reveals Cross Talk of MAP Kinases during Adaptation to Caspofungin Stress in Aspergillus fumigatus

Robert Altwasser; Clara Baldin; Jakob Weber; Reinhard Guthke; Olaf Kniemeyer; Axel A Brakhage; Jörg Linde; Vito Valiante

doi:10.1371/journal.pone.0136932

Network Modeling Reveals Cross Talk of MAP Kinases during Adaptation to Caspofungin Stress in Aspergillus fumigatus

PLoS One. 2015 Sep 10;10(9):e0136932. doi: 10.1371/journal.pone.0136932. eCollection 2015.

Authors

Robert Altwasser¹, Clara Baldin², Jakob Weber², Reinhard Guthke¹, Olaf Kniemeyer³, Axel A Brakhage², Jörg Linde¹, Vito Valiante⁴

Affiliations

¹ Department of Systems Biology/Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Adolf-Reichwein-Str. 23, 07745, Jena, Germany.
² 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.
³ 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.
⁴ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptation, Physiological / drug effects
Adaptation, Physiological / genetics*
Aspergillus fumigatus / drug effects
Aspergillus fumigatus / enzymology*
Aspergillus fumigatus / genetics*
Blotting, Western
Caspofungin
Cell Membrane Permeability / drug effects
Echinocandins / pharmacology*
Gene Expression Profiling
Gene Expression Regulation, Fungal / drug effects
Gene Regulatory Networks / drug effects*
Genes, Fungal
Genetic Association Studies
Lipopeptides
MAP Kinase Signaling System / drug effects
Mitogen-Activated Protein Kinases / metabolism*
Phosphorylation / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
Reproducibility of Results
Software
Stress, Physiological / drug effects
Stress, Physiological / genetics*

Substances

Echinocandins
Lipopeptides
RNA, Messenger
Mitogen-Activated Protein Kinases
Caspofungin

Grants and funding

This work was supported by the ERA-NET PathoGenoMics programme ANTIFUN (The cell wall as a target to improve antifungal therapy against Aspergillosis), BFU2008-04709-E/BMC, (German Federal Ministry of Education and Research: BMBF FKZ 0315439). R.A. was supported by the DFG-founded excellence graduate school Jena School for Microbial Communication (JSMC). J.L. was supported by the DFG-founded CRC/Transregio 124 “FungiNet”. C.B. was supported by the “ARIADNE” Marie Curie Training Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.