Project B4

Image data analysis and agent-based modeling of the spatio-temporal interaction between immune cells and human-pathogenic fungi

Project B4

B4 focuses on the analysis and modeling of image data acquired within the CRC/TR FungiNet. This is accomplished by an image-based systems biology approach consisting of three steps: (i) automated image processing, (ii) derivation of quantitative measures, and (iii) construction of mathematical models to perform predictive computer simulations. The main objective is to advance this approach to investigate the interaction between host immune cells and human-pathogenic fungi, ultimately contributing to the development of a virtual infection model.

In the first funding period, we followed three lines of research: (i) Development of a pipeline for the automated analysis of microscopic images from endpoint experiments to investigate phagocytosis assays for Aspergillus fumigatus (collaboration with A1) and invasion assays for Candida albicans (C1). (ii) Computer simulation of virtual infection models for epithelial invasion of C. albicans (C1) and host-pathogen interactions in human whole-blood (C3). (iii) Mathematical modeling of A. fumigatus infection in the human lung by evolutionary game theory on graphs (A1, B1, C5).

Building on our achievements, in the second funding period we will design new tools and workflows to investigate morphological, functional and dynamic aspects of host-pathogen interactions. For example, the automated analysis of endpoint images will be developed into a comprehensive processing framework of time-resolved image data generated by live cell microscopy. We will also apply advanced computer simulations towards three main goals: (i) the generation of synthetic data representing a well-defined ground truth that we can use to validate our new algorithms for automated image analysis, (ii) the support of the design of experimental assays in order to avoid ambiguities, and (iii) the ability to identify mechanisms that govern the immune response in virtual infection scenarios.

Furthermore, we want to combine Image-based systems biology with the bioinformatics analysis of omics data in order to arrive at a more comprehensive view of infection scenarios across various scales.

Principal Investigator
Author Year Title Journal Links
Valentine M, Rudolph P, Dietschmann A, Tsavou A, Mogavero S, Lee S, Priest EL, Zhurgenbayeva G, Jablonowski N, Timme S, Eggeling C, Allert S, Dolk E, Naglik JR, Figge MT, Gresnigt MS, Hube B 2024 Nanobody-mediated neutralization of candidalysin prevents epithelial damage and inflammatory responses that drive vulvovaginal candidiasis pathogenesis mBio:e0340923 PubMed
Kaden T, Alonso-Roman R, Akbarimoghaddam P, Mosig AS, Graf K, Raasch M, Hoffmann B, Figge MT, Hube B, Gresnigt MS 2024 Modeling of intravenous caspofungin administration using an intestine-on-chip reveals altered Candida albicans microcolonies and pathogenicity. Biomaterials. 9;307:122525 PubMed
Sarkar A, Praetorius JP, Figge MT 2024 Deep learning-based characterization of neutrophil activation phenotypes in ex vivo human Candida blood infections. Struct Biotechnol J. 18;23:1260-1273. PubMed
Alonso-Roman R, Mosig AS, Figge MT , Papenfort K, Eggeling Ch, Schachter FH, Hube B, Gresnigt MS 2024 Organ-on-chip models for infectious disease research. Nat Microbiol 9, 891–904 nature microbiology
Goldmann M, Schmidt F, Cseresnyés Z, Orasch T, Jahreis S, Hartung S, Figge MT, von Lilienfeld-Toal M, Heinekamp T, Brakhage AA 2023 The lipid raft-associated protein stomatin is required for accumulation of dectin-1 in the phagosomal membrane and for full activity of macrophages against Aspergillus fumigatus. mSphere 8(1) :e0052322 PubMed
Orasch T, Gangapurwala G, Vollrath A, González K, Alex J, De San Luis A, Weber C, Hoeppener S, Cseresnyés Z, Figge MT, Guerrero-Sanchez C, Schubert US, Brakhage AA 2023 Polymer-based particles against pathogenic fungi: A non-uptake delivery of compounds. Biomater Adv 146, 213300 PubMed
Jia LJ, Rafiq M, Radosa L, Hortschansky P, Cunha C, Cseresnyés Z, Krüger T, Schmidt F, Heinekamp T, Straßburger M, Löffler B, Doenst T, Lacerda JF, Campos A, Figge MT, Carvalho A, Kniemeyer O, Brakhage AA 2023 Aspergillus fumigatus hijacks human p11 to redirect fungal-containing phagosomes to non-degradative pathway. Cell Host & Microbe: 31,3 Cell Host & Microbe
Gerst R, Cseresnyés Z, Figge MT 2023 JIPipe: visual batch processing for ImageJ. Nat Methods 20(2), 168-169 PubMed
Saffer C, Timme S, Rudolph P, Figge MT 2023 Surrogate infection model predicts optimal alveolar macrophage number for clearance of Aspergillus fumigatus infections. NPJ Syst Biol Appl. 10;9(1):12. PubMed
Praetorius JP, Walluks K, Svensson CM, Arnold D, Figge MT   2023 IMFSegNet: Cost-effective and Objective Quantification of Intramuscular Fat in Histological Sections by Deep Learning. CSBJ2229 CSBJournal
Hoang TNM, Cseresnyés Z, Hartung S, Blickensdorf M, Saffer C, Rennert K, Mosig AS, von Lilienfeld-Toal M, Figge MT 2022 Invasive aspergillosis-on-chip: A quantitative treatment study of human Aspergillus fumigatus infection Biomaterials 283: 121420 PubMed
Belyaev I, Marolda A, Praetorius J-P, Sarkar A, Medyukhina A, Hünniger K, Kurzai O, Figge MT 2022 Automated Characterisation of Neutrophil Activation Phenotypes in Ex Vivo Human Candida Blood Infections. Computational and Structural Biotechnology Journal PubMed
Stanford FA, Matthies N, Cseresnyés Z, Figge MT, Hassan MIA, Voigt K 2021 Expression patterns in reductive iron assimilation and functional consequences during phagocytosis of Lichtheimia corymbifera, an emerging cause of Mucormycosis. J Fungi (Basel) 7: 272 PubMed
Lehnert T, Leonhardt I, Timme S, Thomas-Rüddel D, Bloos F, Sponholz C, Kurzai O, Figge MT, Hünniger K 2021 Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions. Sci Rep 11: 12039 PubMed
Belyaev I, Praetorius JP, Medyukhina A, Figge MT 2021 Enhanced segmentation of label-free cells for automated migration and interaction tracking. Cytometry A 1-12 PubMed
Lehnert T, Prauße MTE, Hünniger K, Praetorius JP, Kurzai O, Figge MT 2021 Comparative assessment of immune evasion mechanisms in human whole-blood infection assays by a systems biology approach. PLoS One 16: e0249372 PubMed
Marolda A, Hünniger K, Böttcher S, Vivas W, Löffler J, Figge MT, Kurzai O 2020 Candida species-dependent release of IL-12 by dendritic cells induces different levels of NK cell stimulation. J Infect Dis 221: 2060-71 PubMed
Shopova IA, Belyaev I, Dasari P, Jahreis S, Stroe MC, Cseresnyés Z, Zimmermann AK, Medyukhina A, Svensson CM, Krüger T, Szeifert V, Nietzsche S, Conrad T, Blango MG, Kniemeyer O, Lilienfeld-Toal Mv, Zipfel PF, Ligeti E, Figge MT, Brakhage AA 2020 Human neutrophils produce antifungal extracellular vesicles against Aspergillus fumigatus. mBio 11: e00596-20 PubMed
Hassan MIA, Kruse J, Krüger T, Dahse HM, Cseresnyés Z, Blango MG, Slevogt H, Hörhold F, Ast V, König R, Figge MT, Kniemeyer O, Brakhage AA, Voigt K 2020 Functional surface proteomic profiling reveals the host heat-shock protein A8 as a mediator of Lichtheimia corymbifera recognition by murine alveolar macrophages. Environ Microbiol 22: 3722-40 PubMed
Cseresnyés Z, Hassan MA, Dahse HD, Voigt K, Figge MT 2020 Quantitative impact of cell membrane fluorescence labeling on phagocytosis measurements in confrontation assays. Front Microbiol 11: 1193 PubMed
Böttcher B, Hoffmann B, Garbe E, Weise T, Cseresnyés Z, Brandt P, Dietrich S, Driesch D, Figge MT, Vylkova S 2020 The transcription factor Stp2 is important for Candida albicans biofilm establishment and sustainability. Front Microbiol 11: 794 PubMed
Tille A, Lehnert T, Zipfel PF, Figge MT 2020 Quantification of factor H mediated self versus non-self discrimination by mathematical modeling. Front Immunol 11: 1911 Frontiers
Blickensdorf M, Timme S+, Figge MT 2020 Hybrid agent-based modeling of Aspergillus fumigatus infection to quantitatively investigate the role of Pores of Kohn in human alveoli. Front Microbiol 11: 1951 PubMed
Lehnert T, Leonhardt I, Timme S, Thomas-Rüddel D, Bloos F, Sponholz C, Kurzai O, Figge MT, Hünniger K 2020 Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions. bioRxiv bioRxiv
Schmidt F, Thywißen A, Goldmann M, Cunha C, Cseresnyés Z, Schmidt H, Rafiq M, Galiani S, Gräler MH, Chamilos G, Lacerda JF, Campos Jr A, Eggeling C, Figge MT, Heinekamp T, Filler SG, Carvalho A, Brakhage AA 2020 Flotillin-dependent membrane microdomains are required for functional phagolysosomes against fungal infections. Cell Rep 32: 108017 PubMed
Hirth G, Svensson CM, Böttcher K, Ullrich S, Figge MT, Jungnickel B 2019 Regulation of the germinal center reaction and somatic hypermutation dynamics by homologous recombination. J Immunol 203: 1493-1501 PubMed
Hassan MIA, Cseresnyés Z, Al-Zaben N, Dahse HM, de Oliveira RJV, Walther G, Voigt K, Figge MT 2019 The geographical region of origin determines the phagocytic vulnerability of Lichtheimia strains. Environ Microbiol 21: 4563-81 PubMed
Dasari P, Koleci N, Shopova I, Wartenberg D, Beyersdorf N, Dietrich S, Sahagún-Ruiz A, Figge MT, Skerka C, Brakhage AA, Zipfel PF 2019 Enolase from Aspergillus fumigatus is a moonlighting and immune evasion protein that binds the human plasma complement protein factors H, FHL-1, C4BP, and Plasminogen. Front Immunol 10: 2573 PubMed
Maurer M, Gresnigt MS, Last A, Wollny T, Berlinghof F, Pospich R, Cseresnyes Z, Medyukhina A, Graf K, Gröger M, Raasch M, Siwczak F, Nietzsche S, Jacobsen ID, Figge MT, Hube B, Huber O, Mosig AS 2019 A three-dimensional immunocompetent intestine-on-chip model as in vitro platform for functional and microbial interaction studies. Biomaterials 220: 119396 PubMed
Blickensdorf M, Timme S, Figge MT 2019 Comparative assessment of aspergillosis by virtual infection modeling in murine and human lung. Front Immunol 10: 142 PubMed
Svensson CM, Shvydkiv O, Dietrich S, Mahler L, Weber T, Choudhary M, Tovar M, Figge MT, Roth M 2019 Coding of experimental conditions in microfluidic droplet assays using colored beads and machine learning supported image analysis. Small 15: e1802384 PubMed
Al-Zaben N, Medyukhina A, Dietrich S, Marolda A, Hünniger K, Kurzai O, Figge MT 2019 Automated tracking of label-free cells with enhanced recognition of whole tracks. Sci Rep 9: 3317 PubMed
Prauße MTE, Lehnert T, Timme S, Hünniger K, Leonhardt I, Kurzai O, Figge MT 2018 Predictive virtual infection modeling of fungal immune evasion in human whole blood. Front Immunol 9: 560 Frontiers
Timme S, Lehnert T, Prauße MTE, Hünniger K, Leonhardt I, Kurzai O, Figge M 2018 Quantitative simulations predict treatment strategies against fungal infections in virtual neutropenic patients. Front Immunol 9: 667 PubMed
Meinel C, Spartà G, Dahse H-M, Hörhold F, König R, Westermann M, Cseresnyés Z, Coldewey SM, Figge MT, Hammerschmidt S, Skerka C, Zipfel PF 2018 Streptococcus pneumoniae from patients with hemolytic uremic syndrome binds human plasminogen via the surface protein PspC and uses plasmin to damage human endothelial cells. J Infect Dis 217: 358-70 PubMed
Cseresnyes Z, Kraibooj K, Figge MT 2018 Hessian-based quantitative image analysis of host-pathogen confrontation assays. Cytometry A 93: 346-56 PubMed
Svensson CM, Medyukhina A, Belyaev I, Al-Zaben N, Figge MT 2018 Untangling cell tracks: Quantifying cell migration by time lapse image data analysis. Cytometry A 93: 357-70 (Review) PubMed
Schaarschmidt B, Vlaic S, Medyukhina A, Neugebauer S, Nietzsche S, Gonnert FA, Rödel J, Singer M, Kiehntopf M, Figge MT, Jacobsen ID, Bauer M, Press AT 2018 Molecular signatures of liver dysfunction are distinct in fungal and bacterial infections in mice. Theranostics 8: 3766-80 PubMed
Allert S*, Förster TM*, Svensson CM, Richardson JP, Pawlik T, Hebecker B, Rudolphi S, Juraschitz M, Schaller M, Blagojevic M, Morschhäuser J, Figge MT, Jacobsen ID, Naglik JR, Kasper L, Mogavero S, Hube B; *authors contributed equally 2018 Candida albicans-induced epithelial damage mediates translocation through intestinal barriers. mBio 9: e00915-18 PubMed
Dasari P, Shopova IA, Stroe M, Wartenberg D, Dahse HM, Beyersdorf N, Hortschansky P, Dietrich S, Cseresnyés Z, Figge MT, Westermann M, Skerka C, Brakhage AA, Zipfel PF 2018 Aspf2 from Aspergillus fumigatus recruits human immune regulators for immune evasion and cell damage. Front Immunol 9: 1635 Frontiers
Brandes S, Dietrich S, Hünniger K, Kurzai O, Figge MT 2017 Migration and interaction tracking for quantitative analysis of phagocyte-pathogen confrontation assays. Med Image Anal 356: 172-83 PubMed
Lehnert T, Figge MT 2017 Dimensionality of motion and binding valency govern receptor-ligand kinetics as revealed by agent-based modeling. Front Immunol 8: 1692 PubMed
Figge MT 2017 Systems Biology of Infection NOVA ACTA LEOPOLDINA (ed.) Crossing Boundaries in Science. Documentation of the Workshop of the German National Academy of Sciences Leopoldina, Weimar, 06/30/2016-07/02/2016, 419, pp. 45-51. Wissenschaftliche Verlagsgesellschaft Stuttgart, Halle (Saale). Leopoldina
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
Buhlmann D, Eberhardt HU, Medyukhina A, Prodinger WM, Figge MT, Zipfel PF, Skerka C 2016 Complement factor H related protein 3 (FHR3) blocks C3d-mediated co-activation of human B cells. J Immunol 197: 620-9 PubMed
Hünniger K, Bieber K, Martin R, Lehnert T, Figge MT, Löffler J, Guo RF, Riedemann NC, Kurzai O 2015 A second stimulus required for enhanced antifungal activity of human neutrophils in blood is provided by anaphylatoxin C5a. J Immunol 194: 1199-210 PubMed
Brandes S, Mokhtari Z, Essig F, Hünniger K, Kurzai O, Figge MT 2015 Automated segmentation and tracking of non-rigid objects in time-lapse microscopy videos of polymorphonuclear neutrophils. Med Image Anal 20: 34-51 PubMed
Duggan S, Essig F, Hünniger K, Mokhtari Z, Bauer L, Lehnert T, Brandes S, Häder A, Jacobsen ID, Martin R, Figge MT, Kurzai O 2015 Neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes. Cell Microbiol 17: 1259-76 PubMed
Lehnert T, Timme S, Pollmächer J, Hünniger K, Kurzai O, Figge MT 2015 Bottom-up modeling approach for the quantitative estimation of parameters in pathogen-host interactions. Front Microbiol 6: 608 PubMed
Medyukhina A, Timme S, Mokhtari Z, Figge MT 2015 Image-based systems biology of infection. Cytometry A 87: 462-70 PubMed
Kraibooj K, Schoeler H, Svensson CM, Brakhage AA, Figge MT 2015 Automated quantification of the phagocytosis of Aspergillus fumigatus conidia by a novel image analysis algorithm. Front Microbiol 6: 549 PubMed
Mattern DJ, Schoeler H, Weber J, Novohradská S, Kraibooj K, Dahse HM, Hillmann F, Valiante V, Figge MT, Brakhage AA 2015 Identification of the antiphagocytic trypacidin gene cluster in the human-pathogenic fungus Aspergillus fumigatus. Appl Microbiol Biotechnol 99: 10151-61 PubMed
Pollmächer J, Figge MT 2015 Deciphering chemokine properties by a hybrid agent-based model of Aspergillus fumigatus infection in human alveoli. Front Microbiol 6: 503 PubMed
Hünniger K, Lehnert T, Bieber K, Martin R, Figge MT, Kurzai O 2014 A virtual infection model quantifies innate effector mechanisms and Candida albicans immune escape in human blood. PLoS Comput Biol 10: e1003479 PubMed
Kraibooj K, Park HR, Dahse HM, Skerka C, Voigt K, Figge MT 2014 Virulent strain of Lichtheimia corymbifera shows increased phagocytosis by macrophages as revealed by automated microscopy image analysis. Mycoses 57 Suppl 3: 56-66 PubMed
Mech F, Wilson D, Lehnert T, Hube B, Figge MT 2014 Epithelial invasion outcompetes hypha development during Candida albicans infection as revealed by an image-based systems biology approach. Cytometry A 85: 126-39 PubMed