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Sandra Timme

About Sandra Timme:
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SEEK ID: https://funginet.hki-jena.de/people/69

Location:  Germany

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FungiNet total
No description specified

Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

Public web page: http://www.funginet.de/home.html

FungiNet B - Bioinformatics projects
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Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

Public web page: http://www.funginet.de/project-area-b.html

FungiNet A - Aspergillus projects
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Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

Public web page: http://www.funginet.de/project-area-a.html

FungiNet C - Candida projects
No description specified

Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

Public web page: http://www.funginet.de/project-area-c.html

B4

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

Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

Public web page: http://www.funginet.de/project-b4.html

State-based model of whole-blood infection assay with PMN-mediated immune evasion mechanism
B4

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

Contributor: Sandra Timme

State-based model of whole-blood infection assays with Candida albicans
B4

The state-based model (SBM) allow to simulate the interplay between innate immune cells, such as monocytes and PMN, and Candida albicans and to quantify immune reaction rates like phagocytosis and killing rates. It is implemented in C++.

Creator: Teresa Lehnert

Contributor: Sandra Timme

DynaCoSys
B4

DynaCoSys models the complement system by using a combination of Ordinary and Partial Differential Equations.

Creators: Teresa Lehnert, Alexander Tille

Contributor: Sandra Timme

Virtual infection model of Aspergillus fumigatus in a murine alveolus
B4

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

Contributor: Sandra Timme

Virtual infection model of Aspergillus fumigatus in a human alveolus
B4

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

Contributor: Sandra Timme

2 hidden items
Quantification of Factor H Mediated Self vs. Non-self Discrimination by Mathematical Modeling.
FungiNet C - Candida projects, B4

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, Teresa Lehnert, Peter Zipfel, Marc Thilo Figge

Date Published: 5th Oct 2020

Journal: Front Immunol

Hybrid Agent-Based Modeling of Aspergillus fumigatus Infection to Quantitatively Investigate the Role of Pores of Kohn in Human Alveoli.
B4

Abstract (Expand)

The healthy state of an organism is constantly threatened by external cues. Due to the daily inhalation of hundreds of particles and pathogens, the immune system needs to constantly accomplish the task … of pathogen clearance in order to maintain this healthy state. However, infection dynamics are highly influenced by the peculiar anatomy of the human lung. Lung alveoli that are packed in alveolar sacs are interconnected by so called Pores of Kohn. Mainly due to the lack of in vivo methods, the role of Pores of Kohn in the mammalian lung is still under debate and partly contradicting hypotheses remain to be investigated. Although it was shown by electron microscopy that Pores of Kohn may serve as passageways for immune cells, their impact on the infection dynamics in the lung is still unknown under in vivo conditions. In the present study, we apply a hybrid agent-based infection model to quantitatively compare three different scenarios and discuss the importance of Pores of Kohn during infections of Aspergillus fumigatus. A. fumigatus is an airborne opportunistic fungus with rising incidences causing severe infections in immunocompromised patients that are associated with high mortality rates. Our hybrid agent-based model incorporates immune cell dynamics of alveolar macrophages - the resident phagocytes in the lung - as well as molecular dynamics of diffusing chemokines that attract alveolar macrophages to the site of infection. Consequently, this model allows a quantitative comparison of three different scenarios and to study the importance of Pores of Kohn. This enables us to demonstrate how passaging of alveolar macrophages and chemokine diffusion affect A. fumigatus infection dynamics. We show that Pores of Kohn alter important infection clearance mechanisms, such as the spatial distribution of macrophages and the effect of chemokine signaling. However, despite these differences, a lack of passageways for alveolar macrophages does impede infection clearance only to a minor extend. Furthermore, we quantify the importance of recruited macrophages in comparison to resident macrophages.

Authors: M. Blickensdorf, Sandra Timme, Marc Thilo Figge

Date Published: 9th Sep 2020

Journal: Front Microbiol

Comparative Assessment of Aspergillosis by Virtual Infection Modeling in Murine and Human Lung.
B4

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, Sandra Timme, Marc Thilo Figge

Date Published: 27th Feb 2019

Journal: Front Immunol

Quantitative Simulations Predict Treatment Strategies Against Fungal Infections in Virtual Neutropenic Patients.
FungiNet C - Candida projects, B4

Abstract (Expand)

The condition of neutropenia, i.e., a reduced absolute neutrophil count in blood, constitutes a major risk factor for severe infections in the affected patients. Candida albicans and Candida glabrata … are opportunistic pathogens and the most prevalent fungal species in the human microbiota. In immunocompromised patients, they can become pathogenic and cause infections with high mortality rates. In this study, we use a previously established approach that combines experiments and computational models to investigate the innate immune response during blood stream infections with the two fungal pathogens C. albicans and C. glabrata. First, we determine immune-reaction rates and migration parameters under healthy conditions. Based on these findings, we simulate virtual patients and investigate the impact of neutropenic conditions on the infection outcome with the respective pathogen. Furthermore, we perform in silico treatments of these virtual patients by simulating a medical treatment that enhances neutrophil activity in terms of phagocytosis and migration. We quantify the infection outcome by comparing the response to the two fungal pathogens relative to non-neutropenic individuals. The analysis reveals that these fungal infections in neutropenic patients can be successfully cleared by cytokine treatment of the remaining neutrophils; and that this treatment is more effective for C. glabrata than for C. albicans.

Authors: Sandra Timme, Teresa Lehnert, M. T. E. Prausse, Kerstin Hünniger, I. Leonhardt, Oliver Kurzai, Marc Thilo Figge

Date Published: 20th Apr 2018

Journal: Front Immunol

Predictive Virtual Infection Modeling of Fungal Immune Evasion in Human Whole Blood.
FungiNet C - Candida projects, B4

Abstract (Expand)

Bloodstream infections by the human-pathogenic fungi Candida albicans and Candida glabrata increasingly occur in hospitalized patients and are associated with high mortality rates. The early immune … response against these fungi in human blood comprises a concerted action of humoral and cellular components of the innate immune system. Upon entering the blood, the majority of fungal cells will be eliminated by innate immune cells, i.e., neutrophils and monocytes. However, recent studies identified a population of fungal cells that can evade the immune response and thereby may disseminate and cause organ dissemination, which is frequently observed during candidemia. In this study, we investigate the so far unresolved mechanism of fungal immune evasion in human whole blood by testing hypotheses with the help of mathematical modeling. We use a previously established state-based virtual infection model for whole-blood infection with C. albicans to quantify the immune response and identified the fungal immune-evasion mechanism. While this process was assumed to be spontaneous in the previous model, we now hypothesize that the immune-evasion process is mediated by host factors and incorporate such a mechanism in the model. In particular, we propose, based on previous studies that the fungal immune-evasion mechanism could possibly arise through modification of the fungal surface by as of yet unknown proteins that are assumed to be secreted by activated neutrophils. To validate or reject any of the immune-evasion mechanisms, we compared the simulation of both immune-evasion models for different infection scenarios, i.e., infection of whole blood with either C. albicans or C. glabrata under non-neutropenic and neutropenic conditions. We found that under non-neutropenic conditions, both immune-evasion models fit the experimental data from whole-blood infection with C. albicans and C. glabrata. However, differences between the immune-evasion models could be observed for the infection outcome under neutropenic conditions with respect to the distribution of fungal cells across the immune cells. Based on these predictions, we suggested specific experimental studies that might allow for the validation or rejection of the proposed immune-evasion mechanism.

Authors: M. T. E. Prausse, Teresa Lehnert, Sandra Timme, Kerstin Hünniger, I. Leonhardt, Oliver Kurzai, Marc Thilo Figge

Date Published: 6th Apr 2018

Journal: Front Immunol

FungiNet Project B4 – Image data analysis and agent-based modelling of the spatio-temporal interaction between immune cells and human-pathogenic fungi
B4

Overview of Project B4 and presentation of a state-based model regarding the immune evasion of C. albicans in human whole-blood infection assays

Creator: Sandra Timme

Contributor: Sandra Timme

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