Project B1

Evolution of fungal virulence with special reference to Candida and Aspergillus

Project Description

Metabolic Pathway Analysis has proven to be valuable for studying microbial metabolism. It allows determine optimal molar yields and study the structural robustness of metabolic networks. Also Evolutionary Game Theory has been very successful in various fields of biology such as microbiology, biochemistry, and systems biology. The project proposed here is based on an innovative combination of the two theories. We will use this combination to (i) detect and investigate consortium pathways that link the pathogenic fungus (Aspergillus fumigatus or Candida albicans) and human cells, (ii) analyse the struggle between fungi and the human immune system by payoff matrices in view of aggressive strategies versus peaceful coexistence and (iii) determine, by analysing the switch between different Nash equilibria, the conditions under which dimorphic fungi make phenotypic transitions and become pathogenic. (iv) The game-theoretical analyses will be extended to a spatially heterogeneous model, in which various human organs will be considered. All the investigations will be made in view of medical applications, for example, to find interventions that support the commensalist life style of the fungi and suppress their pathogenicity. Generated hypotheses are verified experimentally by collaborators in the CRC/Transregio.

Interaction between human host, e.g macrophages and ingested C. albicans cells will be investigated (from Hummert et al., 2010). The latter can use two different strategies: being silent (yeast form, lower cell) or attack the macrophage from inside after transition to the hyphal form (upper cell). Since the attacking cells help the silent cells to escape, their strategy can be considered cooperative. In an evolutionary stable strategy, a fixed proportion of cells will be cooperative (Hummert et al., 2010). Right: Payoff matrix of the symmetric two-player model. In each field, the fitness values of two fungal cells playing against each other are given. l, probability of survival if the macrophage is lysed by fungal cells; c, cost of the attacking strategy.Such and similar “games” will be analysed with special consideration of different, and partly shared metabolic pathways.

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

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
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
Karl S, Dandekar T 2015 Convergence behaviour and control in non-linear biological networks. Sci Rep 5: 9746 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
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
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 pii: S1438-4221(16)30199-0

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
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