State-based model of whole-blood infection assay with PMN-mediated immune evasion mechanism

This model is a variant of the previously developed SBM of whole-blood infection assay. While in the previous model a spontaneous immune evasion mechanism (A) was implemented in this model immune evasion was caused by PMN molecule secretion (B).

Creators: Teresa Lehnert, Maria T. E. Prauße

Submitter: Sandra Timme

Virtual infection model of Aspergillus fumigatus in a murine alveolus

Adaptation of the previously developed virtual infection model of Aspergillus fumigatus in a human alveolus. This model comprises a hybrid agent-based model of a single murine alveolus. The alveolus is represented in a realistic to-scale representation and contains the cell types of alveolar epithelial cells (AEC) of type 1 and 2 as well as the pores of Kohn (PoK). Furthermore, in this model, depending on the infection dose multiple A. fumigatus conidium are inserted into the alveolus and the ...

Creators: Sandra Timme, Marco Blickensdorf

Submitter: Sandra Timme

Virtual infection model of Aspergillus fumigatus in a human alveolus

This model comprises a hybrid agent-based model of a single human alveolus. The alveolus is represented in a realistic to-scale representation and contains the cell types of alveolar epithelial cells (AEC) of type 1 and 2 as well as the pores of Kohn (PoK). A single A. fumigatus conidium in inserted into the alveolus and the AEC, where the conidium is located secretes chemokines. Chemokine secretion is modelled using the partial differential equation of the diffusion equation and numerically ...

Creator: Johannes Pollmächer

Submitter: Sandra Timme

Influence of toxic intermediates on optimal metabolic pathway regulation

Dynamic optimization model to study control points in metabolic pathways to identify general strategies behind pathway regulation. Toxic intermediates determine which enzyme control pathway flux and prevent their accumulation. Therefore those enzymes are drug targets since deregulation leads to self-poisoning of pathogens.

Creator: Jan Ewald

Submitter: Jan Ewald

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[DEMO] Response of hepatocytes to rapid change in the medium composition (gene regulatory network): Model 1100 "freshMedia"

Primary hepatocytes were exposed to a stimulus by exchanging culture medium, thereby simulating changes in the blood composition. The expression of genes at different time points was recorded. Differentially expressed genes were clustered using fuzzy c-means algorithm into five groups. The arcs of the possible network were identified using the NetGenerator algorithm under the restriction of biological knowledge. The analysis was restricted to the main metabolic pathways of hepatocytes. The reverse ...

Creators: Thomas Wolf, Wolfgang Schmidt-Heck, Reinhard Guthke

Submitter: Thomas Wolf

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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

Dimensionality of Motion and Binding Valency Govern Receptor-Ligand Kinetics As Revealed by Agent-Based Modeling.

Abstract (Expand)

Mathematical modeling and computer simulations have become an integral part of modern biological research. The strength of theoretical approaches is in the simplification of complex biological systems. … We here consider the general problem of receptor-ligand binding in the context of antibody-antigen binding. On the one hand, we establish a quantitative mapping between macroscopic binding rates of a deterministic differential equation model and their microscopic equivalents as obtained from simulating the spatiotemporal binding kinetics by stochastic agent-based models. On the other hand, we investigate the impact of various properties of B cell-derived receptors-such as their dimensionality of motion, morphology, and binding valency-on the receptor-ligand binding kinetics. To this end, we implemented an algorithm that simulates antigen binding by B cell-derived receptors with a Y-shaped morphology that can move in different dimensionalities, i.e., either as membrane-anchored receptors or as soluble receptors. The mapping of the macroscopic and microscopic binding rates allowed us to quantitatively compare different agent-based model variants for the different types of B cell-derived receptors. Our results indicate that the dimensionality of motion governs the binding kinetics and that this predominant impact is quantitatively compensated by the bivalency of these receptors.

Authors: T. Lehnert, M. T. Figge

Date Published: 19th Dec 2017

Publication Type: Not specified

Quantification of Factor H Mediated Self vs. Non-self Discrimination by Mathematical Modeling.

Abstract (Expand)

The complement system is part of the innate immune system and plays an important role in the host defense against infectious pathogens. One of the main effects is the opsonization of foreign invaders … and subsequent uptake by phagocytosis. Due to the continuous default basal level of active complement molecules, a tight regulation is required to protect the body's own cells (self cells) from opsonization and from complement damage. A major complement regulator is Factor H, which is recruited from the fluid phase and attaches to cell surfaces where it effectively controls complement activation. Besides self cells, pathogens also have the ability to bind Factor H; they can thus escape opsonization and phagocytosis causing severe infections. In order to advance our understanding of the opsonization process at a quantitative level, we developed a mathematical model for the dynamics of the complement system-termed DynaCoSys model-that is based on ordinary differential equations for cell surface-bound molecules and on partial differential equations for concentration profiles of the fluid phase molecules in the environment of cells. This hybrid differential equation approach allows to model the complement cascade focusing on the role of active C3b in the fluid phase and on the cell surface as well as on its inactivation on the cell surface. The DynaCoSys model enables us to quantitatively predict the conditions under which Factor H mediated complement evasion occurs. Furthermore, investigating the quantitative impact of model parameters by a sensitivity analysis, we identify the driving processes of complement activation and regulation in both the self and non-self regime. The two regimes are defined by a critical Factor H concentration on the cell surface and we use the model to investigate the differential impact of complement model parameters on this threshold value. The dynamic modeling on the surface of pathogens are further relevant to understand pathophysiological situations where Factor H mutants and defective Factor H binding to target surfaces results in pathophysiology such as renal and retinal disease. In the future, this DynaCoSys model will be extended to also enable evaluating treatment strategies of complement-related diseases.

Authors: A. Tille, T. Lehnert, P. F. Zipfel, M. T. Figge

Date Published: 5th Oct 2020

Publication Type: Not specified

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