Game Theory and Cellular Dynamics

The polymorphic yeast Candida albicans and the filamentous fungus Aspergillus fumigatus are the most important life-threatening human pathogenic fungi. Both fungi have developed multiple strategies to attack and evade the human immune system. Using evolutionary game theory and dynamic optimization we analyze the struggle between these fungi and the human immune system. For this we study payoff matrices in view of aggressive strategies versus peaceful coexistence. In an additional study we are using a dynamic population model to under stand the characteristics of an optimal immune response during a fungal infection.

• J. Ewald, P. Sieber, R. Garde, S.N. Lang, S. Schuster, B. Ibrahim
  Trends in mathematical modeling of host-pathogen interactions
  Cell. Mol. Life Sci., 77 (2020) 467–480
• S. Dühring, J. Ewald, S. Germerodt, C. Kaleta, T. Dandekar and S. Schuster
  Modelling the host–pathogen interactions of macrophages and Candida albicans using Game Theory and dynamic optimization
  Journal of The Royal Society Interface 14 (132), 2017, 20170095K.
• Czakai, M. Dittrich, M. Kaltdorf, T. Müller, S. Krappmann, A. Schedler, M. Bonin, S. Dühring, S. Schuster, C. Speth, G. Rambach, H. Einsele, T. Dandekar, J. Löffler
  Influence of platelet-rich plasma on the immune response of human monocyte-derived dendritic cells and macrophages simulated with Aspergillus fumigatus
  International Journal of Medical Microbiology 307 (2), 2017, 95–107
• S. Dühring, S. Germerodt, C. Skerka, P. F. Zipfel, T. Dandekar, S. Schuster
  Host-pathogen interactions between the human innate immune system and Candida albicans - Understanding and modeling defense and evasion strategies
  Frontiers in Microbiology 6 (625), 2015, https://doi.org/10.3389/fmicb.2015.00625External link

DFG Collaborative Research Center / Transregio 124 "FungiNet"

Several pathogenic Ascomycota such as Candida albicans as well as several pathogenic Zygomycota show an interesting phenomenon, which can be considered as deceptive signalling and as molecular mimicry. For example, C. albicans binds human regulators like complement factor H and, thus, hides from the immune system by camouflage. This evasion mechanism is of high medical relevance because it may promote life-threatening fungal infections and may lead, in the case of overresponse, to autoimmune diseases. It also implies a complex immuno-biological decision problem to keep the balance between immunity and autoimmunity. The immune system should minimize the number of false negatives, that is, the pathogens that are not recognized as such, as well as minimize
the number of false positives, that is, own cells that are erroneously attacked. This appears to be a bicriterion problem, and an optimal trade-off must be found.

• S. N. Lang, S. Germerodt, C. Glock, C. Skerka, P. F. Zipfel, S. Schuster
  Molecular crypsis by pathogenic fungi using human factor H - A numerical model
  PLOS One 14, 2019, e0212187
• S. Hummert, C. Glock, S. N. Lang, C. Hummert, C. Skerka, P.F. Zipfel, S. Germerodt, S. Schuster
  Playing hide-and-seek with factor H: Game-theoretical analysis of a single nucleotide polymorphism
  J. Royal Soc. Interface 15, 2018, 20170963
• S. Pande, F. Kaftan, S. Lang, A. Svatos, S. Germerodt, C. Kost
  Privatization of cooperative benefits stabilizes mutualistic cross-feeding interactions in spatially structured environments
  ISME Journal 10, 2016, 1413-1423

Jena School for Microbial Communication (JSMC)

The modelling of microbial interactions in spatially complex environments often poses a challenge for equationbased modelling attempts. Therefore we instead try to use agentbased modelling to generate insights in such systems. For this we collaborate closely with experimental groups in a combination of experimental work and computational simulations to identify the relevant aspects of the microbial interactions in question. I one collaboration we for example investigate the cycles of iron respiration through the bacteria Sideroxydans and Shewanella. Key questions within this context are the identification of optimal strategies for an efficient iron throughput within the cycle and the influence of environmental factors, e. g. the oxygen concentration.

S. Germerodt, K. Bohl, A. Lück, S. Pande, A. Schröter, C. Kaleta, S. Schuster, C. Kost: Pervasive Selection for Cooperative Cross-Feeding in Bacterial Communities, PLOS Computational Biology 12 (2016) e1004986

C. Tokarski, S. Hummert, F. Mech, M.T. Figge, S. Germerodt, A. Schroeter, S. Schuster: Agent-based modeling approach of immune defense against spores of opportunistic human pathogenic fungi, Frontiers in Microbial Immunology 3 (2012) 129

Collaborative Research Center 1127 - Chemical mediators in complex biosystems (ChemBioSys)

Many interactions in nature involve various defense mechanisms. To bypass these mechanisms, there are several counter defense techniques. Examples are provided by beta-lactam antibiotics produced by several fungi and Streptomycetes and, as a counter-adaptation, beta-lactamases (which open the beta-lactam ring) produced by several bacteria.

Another example can be found in Brassicaceae plants, which defend themselves by glucosinolates (GLSs). The stored GLSs are not yet toxic but are hydrolysed by plant myrosinases to isothiocyanates upon herbivory or tissue damage. Specialist herbivores of Brassicaceae have evolved specific counter-defenses. Some of them block myrosinases while others redirect the hydrolysis to form less toxic products (like nitriles).

But everything comes at a price – the counter-defenses imply metabolic costs. Thus, the question arises whether it is always beneficial. Moreover, it is not clear why specialist herbivores primarily choose a toxic habitat where they have to invest into detoxification.

We use game theory, modeling by differential equations and dynamic optimization to describe and explain such phenomena.

• S. Schuster, J. Ewald, T. Dandekar, S. Dühring
  Optimizing defence, counter-defence and counter-counter defence in parasitic and trophic interactions - A modelling study
  arXiv:1907.04820, 2019

 International Max Planck Research School (IMPRS)

Biofilms are an excellent example of ecological interaction among bacteria. Oscillations in biofilms are an emerging topic. At the molecular level, these oscillations are due to metabolite exchange between peripheral and interior cells. We are interested to study the dynamics of these oscillations using mathematical modelling and comparison to various well known oscillators such as the one described by Goodwin.

• R. Garde, J. Ewald, A.T. Kovacs, S. Schuster
  Modelling population dynamics in a unicellular social organism community using a minimal model and evolutionary game theory
  Open Biology 10 (11), 2020, 200206
• R. Garde, B. Ibrahim, S. Schuster
  Extending the minimal model of metabolic oscillations in Bacillus subtilis biofilms
  Scientific Reports 10, 2020, 5579
• R.Garde, B.Ibrahim, Á.T.Kovács, S.Schuster
  Differential equation-based minimal model describing metabolic oscillations in Bacillus subtilis biofilms
  Royal Society Open Science 7, 2020, 190810

 International Max Planck Research School (IMPRS)