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203 Publications visible to you, out of a total of 203
Quantitative Simulations Predict Treatment Strategies Against Fungal Infections in Virtual Neutropenic Patients.

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: S. Timme, T. Lehnert, M. T. E. Prausse, K. Hunniger, I. Leonhardt, O. Kurzai, M. T. Figge

Date Published: 20th Apr 2018

Publication Type: Not specified

Predictive Virtual Infection Modeling of Fungal Immune Evasion in Human Whole Blood.

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, T. Lehnert, S. Timme, K. Hunniger, I. Leonhardt, O. Kurzai, M. T. Figge

Date Published: 6th Apr 2018

Publication Type: Not specified

Proteomics of Aspergillus fumigatus Conidia-containing Phagolysosomes Identifies Processes Governing Immune Evasion.

Abstract (Expand)

Invasive infections by the human pathogenic fungus Aspergillus fumigatus start with the outgrowth of asexual, airborne spores (conidia) into the lung tissue of immunocompromised patients. The resident … alveolar macrophages phagocytose conidia, which end up in phagolysosomes. However, A. fumigatus conidia resist phagocytic degradation to a certain degree. This is mainly attributable to the pigment 1,8-dihydroxynaphthalene (DHN) melanin located in the cell wall of conidia, which manipulates the phagolysosomal maturation and prevents their intracellular killing. To get insight in the underlying molecular mechanisms, we comparatively analyzed proteins of mouse macrophage phagolysosomes containing melanized wild-type (wt) or nonmelanized pksP mutant conidia. For this purpose, a protocol to isolate conidia-containing phagolysosomes was established and a reference protein map of phagolysosomes was generated. We identified 637 host and 22 A. fumigatus proteins that were differentially abundant in the phagolysosome. 472 of the host proteins were overrepresented in the pksP mutant and 165 in the wt conidia-containing phagolysosome. Eight of the fungal proteins were produced only in pksP mutant and 14 proteins in wt conidia-containing phagolysosomes. Bioinformatical analysis compiled a regulatory module, which indicates host processes affected by the fungus. These processes include vATPase-driven phagolysosomal acidification, Rab5 and Vamp8-dependent endocytic trafficking, signaling pathways, as well as recruitment of the Lamp1 phagolysosomal maturation marker and the lysosomal cysteine protease cathepsin Z. Western blotting and immunofluorescence analyses confirmed the proteome data and moreover showed differential abundance of the major metabolic regulator mTOR. Taken together, with the help of a protocol optimized to isolate A. fumigatus conidia-containing phagolysosomes and a potent bioinformatics algorithm, we were able to confirm A. fumigatus conidia-dependent modification of phagolysosomal processes that have been described before and beyond that, identify pathways that have not been implicated in A. fumigatus evasion strategy, yet.Mass spectrometry proteomics data are available via ProteomeXchange with identifiers PXD005724 and PXD006134.

Authors: H. Schmidt, S. Vlaic, T. Kruger, F. Schmidt, J. Balkenhol, T. Dandekar, R. Guthke, O. Kniemeyer, T. Heinekamp, A. A. Brakhage

Date Published: 7th Mar 2018

Publication Type: Not specified

The Definition of Open Reading Frame Revisited.

Abstract (Expand)

The term open reading frame (ORF) is of central importance to gene finding. Surprisingly, at least three definitions are in use. We discuss several molecular biological and bioinformatics aspects, and … we recommend using the definition in which an ORF is bounded by stop codons.

Authors: P. Sieber, M. Platzer, S. Schuster

Date Published: 26th Jan 2018

Publication Type: Not specified

Streptococcus pneumoniae From Patients With Hemolytic Uremic Syndrome Binds Human Plasminogen via the Surface Protein PspC and Uses Plasmin to Damage Human Endothelial Cells.

Abstract (Expand)

Pneumococcal hemolytic uremic syndrome (HUS) in children is caused by infections with Streptococcus pneumoniae. Because endothelial cell damage is a hallmark of HUS, we studied how HUS-inducing pneumococci … derived from infant HUS patients during the acute phase disrupt the endothelial layer. HUS pneumococci efficiently bound human plasminogen. These clinical isolates of HUS pneumococci efficiently bound human plasminogen via the bacterial surface proteins Tuf and PspC. When activated to plasmin at the bacterial surface, the active protease degraded fibrinogen and cleaved C3b. Here, we show that PspC is a pneumococcal plasminogen receptor and that plasmin generated on the surface of HUS pneumococci damages endothelial cells, causing endothelial retraction and exposure of the underlying matrix. Thus, HUS pneumococci damage endothelial cells in the blood vessels and disturb local complement homeostasis. Thereby, HUS pneumococci promote a thrombogenic state that drives HUS pathology.

Authors: C. Meinel, G. Sparta, H. M. Dahse, F. Horhold, R. Konig, M. Westermann, S. M. Coldewey, Z. Cseresnyes, M. T. Figge, S. Hammerschmidt, C. Skerka, P. F. Zipfel

Date Published: 17th Jan 2018

Publication Type: Not specified

ModuleDiscoverer: Identification of regulatory modules in protein-protein interaction networks.

Abstract (Expand)

The identification of disease-associated modules based on protein-protein interaction networks (PPINs) and gene expression data has provided new insights into the mechanistic nature of diverse diseases. … However, their identification is hampered by the detection of protein communities within large-scale, whole-genome PPINs. A presented successful strategy detects a PPIN's community structure based on the maximal clique enumeration problem (MCE), which is a non-deterministic polynomial time-hard problem. This renders the approach computationally challenging for large PPINs implying the need for new strategies. We present ModuleDiscoverer, a novel approach for the identification of regulatory modules from PPINs and gene expression data. Following the MCE-based approach, ModuleDiscoverer uses a randomization heuristic-based approximation of the community structure. Given a PPIN of Rattus norvegicus and public gene expression data, we identify the regulatory module underlying a rodent model of non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD). The module is validated using single-nucleotide polymorphism (SNP) data from independent genome-wide association studies and gene enrichment tests. Based on gene enrichment tests, we find that ModuleDiscoverer performs comparably to three existing module-detecting algorithms. However, only our NASH-module is significantly enriched with genes linked to NAFLD-associated SNPs. ModuleDiscoverer is available at http://www.hki-jena.de/index.php/0/2/490 (Others/ModuleDiscoverer).

Authors: S. Vlaic, T. Conrad, C. Tokarski-Schnelle, M. Gustafsson, U. Dahmen, R. Guthke, S. Schuster

Date Published: 11th Jan 2018

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

Kallikrein Cleaves C3 and Activates Complement.

Abstract (Expand)

The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein-kinin, the coagulation, and the fibrinolytic … systems. Previous work shows that the contact system also activates complement, and that plasma enzymes like kallikrein, plasmin, thrombin, and FXII are involved in the activation process. Here, we show for the first time that kallikrein cleaves the central complement component C3 directly to yield active components C3b and C3a. The cleavage site within C3 is identical to that recognized by the C3 convertase. Also, kallikrein-generated C3b forms C3 convertases, which trigger the C3 amplification loop. Since kallikrein also cleaves factor B to yield Bb and Ba, kallikrein alone can trigger complement activation. Kallikrein-generated C3 convertases are inhibited by factor H; thus, the kallikrein activation pathway merges with the amplification loop of the alternative pathway. Taken together, these data suggest that activation of the contact system locally enhances complement activation on cell surfaces. The human pathogenic microbe Candida albicans activates the contact system in normal human serum. However, C. albicans immediately recruits factor H to the surface, thereby evading the alternative and likely kallikrein-mediated complement pathways.

Authors: S. Irmscher, N. Doring, L. D. Halder, E. A. H. Jo, I. Kopka, C. Dunker, I. D. Jacobsen, S. Luo, H. Slevogt, S. Lorkowski, N. Beyersdorf, P. F. Zipfel, C. Skerka

Date Published: 14th Dec 2017

Publication Type: Not specified

Untangling cell tracks: Quantifying cell migration by time lapse image data analysis.

Abstract (Expand)

Automated microscopy has given researchers access to great amounts of live cell imaging data from in vitro and in vivo experiments. Much focus has been put on extracting cell tracks from such data using … a plethora of segmentation and tracking algorithms, but further analysis is normally required to draw biologically relevant conclusions. Such relevant conclusions may be whether the migration is directed or not, whether the population has homogeneous or heterogeneous migration patterns. This review focuses on the analysis of cell migration data that are extracted from time lapse images. We discuss a range of measures and models used to analyze cell tracks independent of the biological system or the way the tracks were obtained. For single-cell migration, we focus on measures and models giving examples of biological systems where they have been applied, for example, migration of bacteria, fibroblasts, and immune cells. For collective migration, we describe the model systems wound healing, neural crest migration, and Drosophila gastrulation and discuss methods for cell migration within these systems. We also discuss the role of the extracellular matrix and subsequent differences between track analysis in vitro and in vivo. Besides methods and measures, we are putting special focus on the need for openly available data and code, as well as a lack of common vocabulary in cell track analysis. (c) 2017 International Society for Advancement of Cytometry.

Authors: C. M. Svensson, A. Medyukhina, I. Belyaev, N. Al-Zaben, M. T. Figge

Date Published: 5th Oct 2017

Publication Type: Not specified

Two's company: studying interspecies relationships with dual RNA-seq.

Abstract (Expand)

Organisms do not exist isolated from each other, but constantly interact. Cells can sense the presence of interaction partners by a range of receptors and, via complex regulatory networks, specifically … react by changing the expression of many of their genes. Technological advances in next-generation sequencing over the recent years now allow us to apply RNA sequencing to two species at the same time (dual RNA-seq), and thus to directly study the gene expression of two interacting species without the need to physically separate cells or RNA. In this review, we give an overview over the latest studies in interspecies interactions made possible by dual RNA-seq, ranging from pathogenic to symbiotic relationships. We summarize state-of-the-art experimental techniques, bioinformatic data analysis and data interpretation, while also highlighting potential problems and pitfalls starting from the selection of meaningful time points and number of reads to matters of rRNA depletion. A short outlook on new trends in the field of dual RNA-seq concludes this review, looking at sequencing of non-coding RNAs during host-pathogen interactions and the prediction of molecular interspecies interactions networks.

Authors: T. Wolf, P. Kammer, S. Brunke, J. Linde

Date Published: 29th Sep 2017

Publication Type: Not specified

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