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. Stefan Schuster
Prof. Dr. Stefan Schuster

Department of Bioinformatics

Friedrich Schiller University Jena

Author Year Title Journal Links
Dühring S, Schuster S 2024 Studying mixed-species biofilms of Candida albicans and Staphylococcus aureus using evolutionary game theory. PLoS One 19(3):e0297307 PubMed
Salihoglu R, Srivastava M, Liang C, Schilling K, Szalay A, Bencurova E, Dandekar T 2023 PRO-Simat: Protein network simulation and design tool. Com Struc Biotech, 21: 2767-2779 PubMed
Wesp V, Theißen G, Schuster S 2023 Statistical analysis of synonymous and stop codons in pseudo-random and real sequences as a function of GC content. Sci Rep. 13(1):22996. PubMed
Balkenhol J,  Bencurova E, Gupta SK, Schmidt H, Heinekamp T, Brakhage AA,  Pottikkadavath A, Dandekar T 2022 Prediction and validation of host-pathogen interactions by a versatile inference approach using Aspergillus fumigatus as a case study. Computational and Structural Biotechnology Journal 20: 4225-4237 PubMed
Gupta SK, Osmanoglu Ö, Minocha R, Bandi SR, Bencurova E, Srivastava M, Dandekar T. 2022 Genome-wide scan for potential CD4+ T-cell vaccine candidates in Candida auris by exploiting reverse vaccinology and evolutionary information. Front Med 9:1008527 PubMed
Gupta SK, Srivastava M, Osmanoglu Ö, Xu Z, Brakhage AA, Dandekar T 2021 Aspergillus fumigatus versus Genus Aspergillus: Conservation, adaptive evolution, and specific virulence genes. Microorganisms 9: 2014 PubMed
Ewald J, Rivieccio F, Radosa L, Schuster S, Brakhage AA, Kaleta C 2021 Dynamic optimization reveals alveolar epithelial cells as key mediators of host defense in invasive aspergillosis. PLoS Comp Bio 17: e1009645 PubMed
Gupta SK, Ponte-Sucre A, Bencurova E, Dandekar T. 2021 An Ebola, Neisseria and Trypanosoma human protein interaction census reveals a conserved human protein cluster targeted by various human pathogens Comput Struct Biotechnol J.19:5292-5308 PubMed
Naseem M, Gun G, Osmanoglu O, AlRemeithi FA, Iqbal J, Dandekar T 2020 Bacterial shoot apical meristem inoculation assay. Methods Mol Biol 2094: 17-22 PubMed
Naseem M, Srivastava M, Osmanoglu O, Iqbal J, Howari FM, AlRemeithi FA, Dandekar T 2020 Molecular modeling of the interaction between stem cell peptide and immune receptor in plants. Methods Mol Biol 2094: 67-77 PubMed
Naseem M, Osmanoglu O, Iqbal J, Howari FM, AlRemeithi FA, Kaltdorf M, Dandekar T 2020 Mapping a transcriptome-guided Arabidopsis SAM interactome. Methods Mol Biol 2094: 113-8 PubMed
Gupta SK, Srivastava M, Osmanoglu Ö, Dandekar T 2020 Genome-wide inference of the Camponotus floridanus protein-protein interaction network using homologous mapping and interacting domain profile pairs. Sci Rep 10: 2334 PubMed
Garde R, Ewald J, Kovács ÁT, Schuster S 2020 Modelling population dynamics in a unicellular social organism community using a minimal model and evolutionary game theory. Open Biol 10: 200206 PubMed
Srivastava M, Bencurova E, Gupta SK, Weiss E, Löffler J, Dandekar T 2019 Aspergillus fumigatus challenged by human dendritic cells: metabolic and regulatory pathway responses testify a tight battle. Front Cell Infect Microbiol 9: 168 PubMed
Schuster S, Ewald E, Dandekar T, Dühring S 2019 Optimizing defence, counter-defence and counter-counter defence in parasitic and trophic interactions. A modelling study. arXiv 1907.0482 arXiv
Akhoon BA, Gupta SK, Tiwari S, Rathor L, Pant A, Singh N, Gupta SK, Dandekar T, Pandey R 2019 C. elegans protein interaction network analysis probes RNAi validated pro-longevity effect of nhr-6, a human homolog of tumor suppressor Nr4a1. Sci Rep 9: 15711 PubMed
Hamprecht A, Barber AE, Mellinghoff SC, Thelen P, Walther G, Yu Y, Neurgaonkar P, Dandekar T, Cornely OA, Martin R, Kurzai O, on behalf of the German Candida auris Study Group 2019 Candida auris in Germany and previous exposure to foreign healthcare. Emerg Infect Dis 25: 1763-5 PubMed
Ewald J, Sieber P, Garde R, Lang SN, Schuster S, Ibrahim B 2019 Trends in mathematical modeling of host-pathogen interactions. Cell Mol Life Sci 77: 467-80 (Review) PubMed
Lang SN, Germrodt S, Glock C, Skerka C, Zipfel PF, Schuster S 2019 Molecular crypsis by pathogenic fungi using human factor H. A numerical model. PLoS One 14: e0212187 PubMed
Sieber P, Platzer M, Schuster S 2018 The definition of open reading frame revisited. Trends Genet 34: 167-70 PubMed
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 PubMed
Naseem M, Bencurova E, Dandekar T 2018 The cytokinin-activating LOG-family proteins are not lysine decarboxylases. Trends Biochem Sci 43: 232-6 (Review) PubMed
Sieber P, Voigt K, Kämmer P, Brunke S, Schuster S, Linde L 2018 Comparative study on alternative splicing in human fungal pathogens suggests its involvement during host invasion. Front Microbiol 9: 2313 Front Microbiol
Naseem M, Kunz M, Dandekar T 2017 Plant-pathogen maneuvering over apoplastic sugars. Trends Plant Sci 22: 740-3 (Review) 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 optimization. J R Soc Interface 14: 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