Project B1

Evolution of fungal virulence with special reference to Candida and Aspergillus

Analysis methods to model and investigate evolution of fungal virulence with special reference to Candida and Aspergillus.
Analysis methods to model and investigate evolution of fungal virulence with special reference to Candida and Aspergillus.

Project B1 is aimed at elucidating the evolution of fungal virulence by bioinformatics and systems biology methods. It is based on an innovative combination of Metabolic Pathway Analysis, optimization approaches and Evolutionary Game Theory.

In the first funding period, Metabolic Pathway Analysis was successfully used to elucidate fungal metabolism. Game-theoretical models in combination with dynamic optimization were established and employed to explain the different outcomes after ingestion of Candida albicans cells by macrophages and the struggle between Aspergillus fumigatus and the host in lung alveoli. A basic model for predicting under which circumstances counter-counter defenses by the host are useful was established. We also established specific models for those parts of the metabolism of A. fumigatus and C. albicans that are of interest for further analysis, for example, for iron-limiting conditions and the interaction with dendritic cells. Building on this, we currently approach the direct struggle and molecular interactions between the host and fungus more quantitatively, applying different modeling tools and testing hypotheses, such as on cytokinins and the evolutionary history of fungus-amoebae interaction as a pathogenicity ’school’. Our mathematical models enable, in the second period, experiments by which the role of biochemical pathways and regulatory proteins on both sides can be elucidated.

We will model host responses of different cell types (neutrophils, macrophages, T cells) quantitatively and optimal fungal strategies (counter defense vs. attack) in dependence on benefit-to-cost ratios. The intended work on A. fumigatus will use metabolic and general pathway analysis in combination with evolutionary game theory for optimization and experimental testing to study the evolution of robustness and regulation of A. fumigatus virulence and host defense. We want to better understand the potential of rewiring, the pathways required for each strategy implementation, and how different environmental settings, including confrontation and survival strategies can affect the dynamics.

Principal Investigators
Prof. Dr. Thomas Dandekar
Prof. Dr. Thomas Dandekar

Biocenter, Department of Bioinformatics and Research Center for Infectious Diseases (ZINF)  

Julius Maximilians University Würzburg

dandekar@biozentrum.uni-wuerzburg.de

Prof. Dr. Stefan Schuster
Prof. Dr. Stefan Schuster

Department of Bioinformatics

Friedrich Schiller University Jena

stefan.schu@uni-jena.de

Publications
Author Year Title Journal Links
Sieber P, Platzer M, Schuster S 2018 The definition of open reading frame revisited. Trends Genet 34: 167-70 Science Direct
Vlaic S, Conrad T, Tokarski-Schnelle C, Gustafsson M, Dahmen U, Reinhard Guthke R, Schuster S 2018 ModuleDiscoverer: Identification of regulatory modules in protein-protein interaction networks. Sci Rep 8: 433 PubMed
Hummert S, Glock C, Lang SN, Hummert C, Skerka C, Zipfel PF, Germerodt S, Schuster S 2018 Playing ’hide-and-seek’ with factor H: game-theoretical analysis of a single nucleotide polymorphism. J R Soc Interface 15: 20170963 Royal Society Publishing
Naseem M, Bencurova E, Dandekar T 2018 The cytokinin-activating LOG-family proteins are not lysine decarboxylases. Trends Biochem Sci 43: 232-6 PubMed
Schuster S, Fichtner M, Sasso S 2017 Use of fibonacci numbers in lipidomics - Enumerating various classes of fatty acids. Sci Rep 7: 39821 PubMed
Dühring S, Ewald J, Germerodt S, Kaleta C, Dandekar T, Schuster S 2017 Modelling the host-pathogen interactions of macrophages and Candida albicans using game theory and dynamic optimisation. J R Soc Interface 14: pii: 20170095 PubMed
Prauße MT, Schäuble S, Guthke R, Schuster S 2016 Computing the various pathways of penicillin synthesis and their molar yields. Biotechnol Bioeng 113: 173-81 PubMed
Pollmächer J, Timme S, Schuster S, Brakhage AA, Zipfel PF, Figge MT 2016 Deciphering the counterplay of Aspergillus fumigatus infection and host inflammation by evolutionary games on graphs. Sci Rep 6: 27807 PubMed
Czakai K, Dittrich M, Kaltdorf M, Müller T, Krappmann S, Schedler A, Bonin M, Dühring S, Schuster S, Speth C, Rambach G, Einsele H, Dandekar T, Löffler J 2016 Influence of platelet-rich plasma on the immune response of human monocyte-derived dendritic cells and macrophages stimulated with Aspergillus fumigatus. Int J Med Microbiol 307: 95-107 PubMed
Othman EM, Nassem M, Awad E, Dandekar T, Stopper H 2016 The plant hormone cytokinin confers protection against oxidative stress in mammalian cells. PLoS One 11: e0168386 PubMed
Dühring S, Germerodt S, Skerka C, Zipfel PF, Dandekar T, Schuster S 2015 Host-pathogen interactions between the human innate immune system and Candida albicans - understanding and modeling defense and evasion strategies. Front Microbiol 6: 625 Frontiers
Karl S, Dandekar T 2015 Convergence behaviour and control in non-linear biological networks. Sci Rep 5: 9746 PubMed
Srivastava M, Malviya N, Dandekar T 2015 Application of biotechnology and bioinformatics tools in plant-fungus interactions. Bahadur B, Rajam MV, Sahijram L, Krishnamurthy KV (eds.) Plant Biol Biotechnology, pp. 49-64. Springer India.  
Naseem M, Sarukhanyan E, Dandekar T 2015 LONELY-GUY knocks every door: Crosskingdom microbial pathogenesis. Trends Plant Sci 20: 781-3 PubMed
Naseem M, Kaltdorf M, Dandekar T 2015 The nexus between growth and defence signaling: auxin and cytokinin modulate plant immune response pathways. J Exp Bot 66: 4885-96 PubMed
Naseem M, Srivastava M, Dandekar T 2014 Stem-cell-triggered immunity safeguards cytokinin enriched plant shoot apexes from pathogen infection. Front Plant Sci 5: 588 PubMed