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2 Publications visible to you, out of a total of 2
Comparative Assessment of Aspergillosis by Virtual Infection Modeling in Murine and Human Lung.

Abstract (Expand)

Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen that can cause severe infections in immunocompromised patients. Conidia that reach the lower respiratory tract are confronted with … alveolar macrophages, which are the resident phagocytic cells, constituting the first line of defense. If not efficiently removed in time, A. fumigatus conidia can germinate causing severe infections associated with high mortality rates. Mice are the most extensively used model organism in research on A. fumigatus infections. However, in addition to structural differences in the lung physiology of mice and the human host, applied infection doses in animal experiments are typically orders of magnitude larger compared to the daily inhalation doses of humans. The influence of these factors, which must be taken into account in a quantitative comparison and knowledge transfer from mice to humans, is difficult to measure since in vivo live cell imaging of the infection dynamics under physiological conditions is currently not possible. In the present study, we compare A. fumigatus infection in mice and humans by virtual infection modeling using a hybrid agent-based model that accounts for the respective lung physiology and the impact of a wide range of infection doses on the spatial infection dynamics. Our computer simulations enable comparative quantification of A. fumigatus infection clearance in the two hosts to elucidate (i) the complex interplay between alveolar morphometry and the fungal burden and (ii) the dynamics of infection clearance, which for realistic fungal burdens is found to be more efficiently realized in mice compared to humans.

Authors: M. Blickensdorf, S. Timme, M. T. Figge

Date Published: 27th Feb 2019

Publication Type: Not specified

Deciphering chemokine properties by a hybrid agent-based model of Aspergillus fumigatus infection in human alveoli.

Abstract (Expand)

The ubiquitous airborne fungal pathogen Aspergillus fumigatus is inhaled by humans every day. In the lung, it is able to quickly adapt to the humid environment and, if not removed within a time frame … of 4-8 h, the pathogen may cause damage by germination and invasive growth. Applying a to-scale agent-based model of human alveoli to simulate early A. fumigatus infection under physiological conditions, we recently demonstrated that alveolar macrophages require chemotactic cues to accomplish the task of pathogen detection within the aforementioned time frame. The objective of this study is to specify our general prediction on the as yet unidentified chemokine by a quantitative analysis of its expected properties, such as the diffusion coefficient and the rates of secretion and degradation. To this end, the rule-based implementation of chemokine diffusion in the initial agent-based model is revised by numerically solving the spatio-temporal reaction-diffusion equation in the complex structure of the alveolus. In this hybrid agent-based model, alveolar macrophages are represented as migrating agents that are coupled to the interactive layer of diffusing molecule concentrations by the kinetics of chemokine receptor binding, internalization and re-expression. Performing simulations for more than a million virtual infection scenarios, we find that the ratio of secretion rate to the diffusion coefficient is the main indicator for the success of pathogen detection. Moreover, a subdivision of the parameter space into regimes of successful and unsuccessful parameter combination by this ratio is specific for values of the migration speed and the directional persistence time of alveolar macrophages, but depends only weakly on chemokine degradation rates.

Authors: J. Pollmacher, M. T. Figge

Date Published: 16th Jun 2015

Publication Type: Not specified

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