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74 Publications visible to you, out of a total of 74
Facing the challenges of multiscale modelling of bacterial and fungal pathogen-host interactions

Abstract (Expand)

Recent and rapidly evolving progress on high-throughput measurement techniques and computational performance has led to the emergence of new disciplines, such as systems medicine and translational … systems biology. At the core of these disciplines lies the desire to produce multiscale models: mathematical models that integrate multiple scales of biological organization, ranging from molecular, cellular and tissue models to organ, whole-organism and population scale models. Using such models, hypotheses can systematically be tested. In this review, we present state-of-the-art multiscale modelling of bacterial and fungal infections, considering both the pathogen and host as well as their interaction. Multiscale modelling of the interactions of bacteria, especially Mycobacterium tuberculosis, with the human host is quite advanced. In contrast, models for fungal infections are still in their infancy, in particular regarding infections with the most important human pathogenic fungi, Candida albicans and Aspergillus fumigatus. We reflect on the current availability of computational approaches for multiscale modelling of host-pathogen interactions and point out current challenges. Finally, we provide an outlook for future requirements of multiscale modelling.

Authors: J. Schleicher, , M. Gustafsson, G. Cedersund, ,

Date Published: 10th Feb 2016

Publication Type: Not specified

Editorial: Computational Systems Biology of Pathogen-Host Interactions

Abstract

Not specified

Authors: S. Durmus, T. Cakir,

Date Published: 4th Feb 2016

Publication Type: Not specified

Candida albicans infection leads to barrier breakdown and a MAPK/NF-kappaB mediated stress response in the intestinal epithelial cell line C2BBe1

Abstract (Expand)

Intestinal epithelial cells (IEC) form a tight barrier to the gut lumen. Paracellular permeability of the intestinal barrier is regulated by tight junction proteins and can be modulated by microorganisms … and other stimuli. The polymorphic fungus Candida albicans, a frequent commensal of the human mucosa has the capacity of traversing this barrier and establishing systemic disease within the host. Infection of polarized C2BBe1 IEC with wild-type C. albicans led to a transient increase of transepithelial electric resistance (TEER) before subsequent barrier disruption, accompanied by a strong decline of junctional protein levels and substantial, but considerably delayed cytotoxicity. Time-resolved microarray-based transcriptome analysis of C. albicans challenged IEC revealed a prominent role of NF-kappaB and MAPK signaling pathways in the response to infection. Hence, we inferred a gene regulatory network based on differentially expressed NF-kappaB and MAPK pathway components and their predicted transcriptional targets. The network model predicted activation of GDF15 by NF-kappaB was experimentally validated. Furthermore, inhibition of NF-kappaB activation in C. albicans infected C2BBe1 cells led to enhanced cytotoxicity in the epithelial cells. Taken together our study identifies NF-kappaB activation as an important protective signaling pathway in the response of epithelial cells to C. albicans. This article is protected by copyright. All rights reserved.

Authors: M. Bohringer, S. Pohlers, , , J. Piegsa, M. Weber, R. Martin, , , ,

Date Published: 12th Jan 2016

Publication Type: Not specified

Network Modeling Reveals Cross Talk of MAP Kinases during Adaptation to Caspofungin Stress in Aspergillus fumigatus

Abstract (Expand)

Mitogen activated protein kinases (MAPKs) are highly conserved in eukaryotic organisms. In pathogenic fungi, their activities were assigned to different physiological functions including drug adaptation … and resistance. Aspergillus fumigatus is a human pathogenic fungus, which causes life-threatening invasive infections. Therapeutic options against invasive mycoses are still limited. One of the clinically used drugs is caspofungin, which specifically targets the fungal cell wall biosynthesis. A systems biology approach, based on comprehensive transcriptome data sets and mathematical modeling, was employed to infer a regulatory network and identify key interactions during adaptation to caspofungin stress in A. fumigatus. Mathematical modeling and experimental validations confirmed an intimate cross talk occurring between the cell wall-integrity and the high osmolarity-glycerol signaling pathways. Specifically, increased concentrations of caspofungin promoted activation of these signalings. Moreover, caspofungin affected the intracellular transport, which caused an additional osmotic stress that is independent of glucan inhibition. High concentrations of caspofungin reduced this osmotic stress, and thus decreased its toxic activity. Our results demonstrated that MAPK signaling pathways play a key role during caspofungin adaptation and are contributing to the paradoxical effect exerted by this drug.

Authors: R. Altwasser, C. Baldin, J. Weber, , O. Kniemeyer, , , V. Valiante

Date Published: 10th Sep 2015

Publication Type: Not specified

Draft Genome Sequence of the Fungus Penicillium brasilianum MG11

Abstract (Expand)

The genus Penicillium belongs to the phylum Ascomycota and includes a variety of fungal species important for food and drug production. We report the draft genome sequence of Penicillium brasilianum … MG11. This strain was isolated from soil, and it was reported to produce different secondary metabolites.

Authors: F. Horn, , D. J. Mattern, G. Walther, , , V. Valiante

Date Published: 5th Sep 2015

Publication Type: Not specified

Computing the various pathways of penicillin synthesis and their molar yields

Abstract (Expand)

More than 80 years after its discovery, penicillin is still a widely used and commercially highly important antibiotic. Here, we analyse the metabolic network of penicillin synthesis in Penicillium … chrysogenum based on the concept of elementary flux modes. In particular, we consider the synthesis of the invariant molecular core of the various subtypes of penicillin and the two major ways of incorporating sulfur: transsulfuration and direct sulfhydrylation. 66 elementary modes producing this invariant core are obtained. These show four different yields with respect to glucose, notably (1/2), 2/5, 1/3, and 2/7, with the highest yield of (1/2) occurring only when direct sulfhydrylation is used and alpha-aminoadipate is completely recycled. In the case of no recycling of this intermediate, we find the maximum yield to be 2/7. We compare these values with earlier literature values. Our analysis provides a systematic overview of the redundancy in penicillin synthesis and a detailed insight into the corresponding routes. Moreover, we derive suggestions for potential knockouts that could increase the average yield.

Authors: M. T. Prausse, S. Schauble, ,

Date Published: 19th Aug 2015

Publication Type: Not specified

Integrated inference and evaluation of host-fungi interaction networks

Abstract (Expand)

Fungal microorganisms frequently lead to life-threatening infections. Within this group of pathogens, the commensal Candida albicans and the filamentous fungus Aspergillus fumigatus are by far the most … important causes of invasive mycoses in Europe. A key capability for host invasion and immune response evasion are specific molecular interactions between the fungal pathogen and its human host. Experimentally validated knowledge about these crucial interactions is rare in literature and even specialized host-pathogen databases mainly focus on bacterial and viral interactions whereas information on fungi is still sparse. To establish large-scale host-fungi interaction networks on a systems biology scale, we develop an extended inference approach based on protein orthology and data on gene functions. Using human and yeast intraspecies networks as template, we derive a large network of pathogen-host interactions (PHI). Rigorous filtering and refinement steps based on cellular localization and pathogenicity information of predicted interactors yield a primary scaffold of fungi-human and fungi-mouse interaction networks. Specific enrichment of known pathogenicity-relevant genes indicates the biological relevance of the predicted PHI. A detailed inspection of functionally relevant subnetworks reveals novel host-fungal interaction candidates such as the Candida virulence factor PLB1 and the anti-fungal host protein APP. Our results demonstrate the applicability of interolog-based prediction methods for host-fungi interactions and underline the importance of filtering and refinement steps to attain biologically more relevant interactions. This integrated network framework can serve as a basis for future analyses of high-throughput host-fungi transcriptome and proteome data.

Authors: , C. H. Luther, J. Balkenhol, , ,

Date Published: 4th Aug 2015

Publication Type: Not specified

Host-pathogen interactions between the human innate immune system and Candida albicans-understanding and modeling defense and evasion strategies

Abstract (Expand)

The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long … time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.

Authors: , S. Germerodt, , , ,

Date Published: 30th Jun 2015

Publication Type: Not specified

Bottom-up modeling approach for the quantitative estimation of parameters in pathogen-host interactions

Abstract (Expand)

Opportunistic fungal pathogens can cause bloodstream infection and severe sepsis upon entering the blood stream of the host. The early immune response in human blood comprises the elimination of pathogens … by antimicrobial peptides and innate immune cells, such as neutrophils or monocytes. Mathematical modeling is a predictive method to examine these complex processes and to quantify the dynamics of pathogen-host interactions. Since model parameters are often not directly accessible from experiment, their estimation is required by calibrating model predictions with experimental data. Depending on the complexity of the mathematical model, parameter estimation can be associated with excessively high computational costs in terms of run time and memory. We apply a strategy for reliable parameter estimation where different modeling approaches with increasing complexity are used that build on one another. This bottom-up modeling approach is applied to an experimental human whole-blood infection assay for Candida albicans. Aiming for the quantification of the relative impact of different routes of the immune response against this human-pathogenic fungus, we start from a non-spatial state-based model (SBM), because this level of model complexity allows estimating a priori unknown transition rates between various system states by the global optimization method simulated annealing. Building on the non-spatial SBM, an agent-based model (ABM) is implemented that incorporates the migration of interacting cells in three-dimensional space. The ABM takes advantage of estimated parameters from the non-spatial SBM, leading to a decreased dimensionality of the parameter space. This space can be scanned using a local optimization approach, i.e., least-squares error estimation based on an adaptive regular grid search, to predict cell migration parameters that are not accessible in experiment. In the future, spatio-temporal simulations of whole-blood samples may enable timely stratification of sepsis patients by distinguishing hyper-inflammatory from paralytic phases in immune dysregulation.

Authors: T. Lehnert, , J. Pollmacher, , ,

Date Published: 19th Jun 2015

Publication Type: Not specified

Automated quantification of the phagocytosis of Aspergillus fumigatus conidia by a novel image analysis algorithm

Abstract (Expand)

Studying the pathobiology of the fungus Aspergillus fumigatus has gained a lot of attention in recent years. This is due to the fact that this fungus is a human pathogen that can cause severe diseases, … like invasive pulmonary aspergillosis in immunocompromised patients. Because alveolar macrophages belong to the first line of defense against the fungus, here, we conduct an image-based study on the host-pathogen interaction between murine alveolar macrophages and A. fumigatus. This is achieved by an automated image analysis approach that uses a combination of thresholding, watershed segmentation and feature-based object classification. In contrast to previous approaches, our algorithm allows for the segmentation of individual macrophages in the images and this enables us to compute the distribution of phagocytosed and macrophage-adherent conidia over all macrophages. The novel automated image-based analysis provides access to all cell-cell interactions in the assay and thereby represents a framework that enables comprehensive computation of diverse characteristic parameters and comparative investigation for different strains. We here apply automated image analysis to confocal laser scanning microscopy images of the two wild-type strains ATCC 46645 and CEA10 of A. fumigatus and investigate the ability of macrophages to phagocytose the respective conidia. It is found that the CEA10 strain triggers a stronger response of the macrophages as revealed by a higher phagocytosis ratio and a larger portion of the macrophages being active in the phagocytosis process.

Authors: K. Kraibooj, , C. M. Svensson, ,

Date Published: 9th Jun 2015

Publication Type: Not specified

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