Project B2

Signaling molecules as entry tickets for infection networks in Aspergillus fumigatus and Candida albicans human infection

How do Aspergillus fumigatus and Candida albicans enter the human host? Do they have specific signaling molecules used as entry tickets and if so, how are the subsequent interactions formed, modified and changed over time? We investigate these questions in B2.

We have established large-scale host-pathogen interaction networks of C. albicans and A. fumigatus and human and mouse by orthologue predictions of host pathogen interactions from other organisms. This has predicted novel interactions, such as between enolase (Candida) and Cd4 (mouse) as well as pry family cell wall protein (Aspergillus) and caveolin (human integral membrane protein). Several host pathogen predictions have been confirmed. In the second funding period, fungal signaling and connected pathways will be studied with focus on how these signals pave the way to infection. A comprehensive database of fungal host pathogen signaling and downstream signaling pathways will be established. Host- and pathogen-specific modules as well as interconnected host-pathogen interaction modules will be analyzed. Component assembly will first lead to Boolean networks and then to prediction of network effects, analysis of their connectivity, system behaviour and states, followed by semi-quantitative dynamical modeling. Predicted interactions, signaling and fungal responses will be experimentally tested for A. fumigatus and C. albicans in collaboration with Z2 (Kniemeyer) to reveal early and late signaling events in infection. Furthermore, novel algorithms will be developed for data-driven analysis of integrated host-pathogen interaction networks to identify nodes and modules that are central for early and late signal processing of connected host and pathogen responses. For validation of all predictions, experimental data on signaling (collaboration with C2) and cellular response signaling (collaboration with A2) will be incorporated. Next, predicted modules and signaling cascades will be refined in iterative cycles of theory and experiment. Detailed systems-biology studies will investigate host immune cell signaling, starting from dendritic cells and macrophages, and then considering neutrophils (with A1), B cells (with C4) and T-cells (with A4).

A close view on the infection using signaling networks based on proteome data (collaboration A1 (Brakhage) and Z2 (Kniemeyer): Interactome of neutrophils (A, left) and of A. fumigatus (B, right). The direction of regulation is encapsulated by color (up, red or down regulated proteins). Furthermore, directly interacting proteins were also calculated (not shown) and are in addition available from our database.

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

Dr. Dr. Marcus Dittrich
Dr. Dr. Marcus Dittrich

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

Julius Maximilians University Würzburg

marcus.dittrich@biozentrum.uni-wuerzburg.de

Publications
Author Year Title Journal Links
Schmidt H, Vlaic S, Krüger T, Schmidt F, Balkenhohl J, Dandekar T, Guthke R, Kniemeyer O, Heinekamp T, Brakhage AA 2018 Proteomics of Aspergillus fumigatus conidia-containing phagolysosomes identifies processes governing immune evasion. Mol Cell Proteomics 17: 1084-96 PubMed
Bencurova E, Gupta SK, Sarukhanyan E, Dandekar 2018 Identification of antifungal targets based on computer modeling. J Fungi 4 pii: E81 (review) PubMed
Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, Rasche L, Hartmann E, Dandekar T, Einsele H, Topp M 2017 Frequency of regulatory T cells determines the outcome of the T cell engaging antibody blinatumomab in patients with B precursor ALL. Leukemia 31: 2181-90 PubMed
Ewald J, Bartl M, Dandekar T, Kaleta C 2017 Optimality principles reveal a complex interplay of intermediate toxicity and kinetic efficiency in the regulation of prokaryotic metabolism. PLoS Comput Biol 13: e1005371 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
Ewald J, Bartl M, Kaleta C 2017 Deciphering the regulation of metabolism with dynamic optimization: an overview of recent advances. Biochem Soc Trans pii: BST20170137 PubMed
Wurster S, Thielen V, Weis P, Walther P, Elias J, Waaga-Gasser AM, Dragan M, Dandekar T, Einsele H, Löffler J, Ullmann, AJ 2017 Mucorales spores induce a proinflammatory cytokine response in human mononuclear phagocytes and harbor no rodlet hydrophobins. Virulence 8: 1708-18 PubMed
Gupta SK, Gross R, Dandekar T 2016 An antibiotic target ranking and prioritization pipeline ombining sequence, structure and network-based approaches exemplified for Serratia marcescens. Gene 591: 268-78 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
Remmele WC, Luther C, Balkenhol J, Dandekar T, Mueller T, Dittrich MT 2015 Integrated inference and evaluation of host-fungi interaction networks. Front Micobiol 6: 764 Frontiers
Ewald J, Kötzing M, Bartl M, Kaleta C 2015 Footprints of optimal protein assembly strategies in the operonic structure of prokaryotes. Metabolites 5: 252-69 PubMed
de Hijas-Liste GM, Balsa-Canto E, Ewald J, Bartl M, Li P, Banga JR, Kaleta C 2015 Optimal programs of pathway control: dissecting the influence of pathway topology and feedback inhibition on pathway regulation. BMC Bioinformatics 16: 163 BMC Bioinformatics
Morton CO, Fliesser M, Dittrich M, Mueller T, Bauer R, Kneitz S, Hope W, Rogers TR, Einsele H, Loeffler J 2014 Gene expression profiles of human dendritic cells interacting with Aspergillus fumigatus in a bilayer model of the alveolar epithelium/endothelium interface. PLoS One 9: e98279 PubMed
Boyanova D, Nilla S, Klau GW, Dandekar T, Muller T, Dittrich M 2014 Functional module search in protein networks based on semantic similarity improves the analysis of proteomics data. Mol Cell Proteomics 13: 1877-89 PubMed