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.