title: A virtual infection model quantifies innate effector mechanisms and Candida albicans immune escape in human blood.
abstract: Candida albicans bloodstream infection is increasingly frequent and can result in disseminated candidiasis associated with high mortality rates. To analyze the innate immune response against C. albicans, fungal cells were added to human whole-blood samples. After inoculation, C. albicans started to filament and predominantly associate with neutrophils, whereas only a minority of fungal cells became attached to monocytes. While many parameters of host-pathogen interaction were accessible to direct experimental quantification in the whole-blood infection assay, others were not. To overcome these limitations, we generated a virtual infection model that allowed detailed and quantitative predictions on the dynamics of host-pathogen interaction. Experimental time-resolved data were simulated using a state-based modeling approach combined with the Monte Carlo method of simulated annealing to obtain quantitative predictions on a priori unknown transition rates and to identify the main axis of antifungal immunity. Results clearly demonstrated a predominant role of neutrophils, mediated by phagocytosis and intracellular killing as well as the release of antifungal effector molecules upon activation, resulting in extracellular fungicidal activity. Both mechanisms together account for almost [Formula: see text] of C. albicans killing, clearly proving that beside being present in larger numbers than other leukocytes, neutrophils functionally dominate the immune response against C. albicans in human blood. A fraction of C. albicans cells escaped phagocytosis and remained extracellular and viable for up to four hours. This immune escape was independent of filamentation and fungal activity and not linked to exhaustion or inactivation of innate immune cells. The occurrence of C. albicans cells being resistant against phagocytosis may account for the high proportion of dissemination in C. albicans bloodstream infection. Taken together, iterative experiment-model-experiment cycles allowed quantitative analyses of the interplay between host and pathogen in a complex environment like human blood.
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hünniger
authors.affiliation: Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany ; Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lehnert
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Bieber
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany.
authors.forename: Ronny
authors.initials: R
authors.lastname: Martin
authors.affiliation: Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany ; Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Marc Thilo
authors.initials: MT
authors.lastname: Figge
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kurzai
mesh_terms: D002176:Candida albicans / Q000276:immunology / Q000472:pathogenicity; D058387:Candidemia / Q000097:blood / Q000276:immunology* / Q000382:microbiology; D019295:Computational Biology; D003198:Computer Simulation; D003428:Cross Infection / Q000097:blood / Q000276:immunology / Q000382:microbiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D055641:Mathematical Concepts; D018448:Models, Immunological; D009000:Monocytes / Q000276:immunology; D009010:Monte Carlo Method; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis; D014584:User-Computer Interface