Publications by authors named "Reinhard Guthke"

105 Publications

Survival Strategies of Pathogenic Species in Human Blood Show Independent and Specific Adaptations.

mBio 2020 10 6;11(5). Epub 2020 Oct 6.

Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany

Only four species, , , , and , together account for about 90% of all bloodstream infections and are among the most common causes of invasive fungal infections of humans. However, virulence potential varies among these species, and the phylogenetic tree reveals that their pathogenicity may have emerged several times independently during evolution. We therefore tested these four species in a human whole-blood infection model to determine, via comprehensive dual-species RNA-sequencing analyses, which fungal infection strategies are conserved and which are recent evolutionary developments. The infection progressed from initial immune cell interactions to nearly complete killing of all fungal cells. During the course of infection, we characterized important parameters of pathogen-host interactions, such as fungal survival, types of interacting immune cells, and cytokine release. On the transcriptional level, we obtained a predominantly uniform and species-independent human response governed by a strong upregulation of proinflammatory processes, which was downregulated at later time points after most of the fungal cells were killed. In stark contrast, we observed that the different fungal species pursued predominantly individual strategies and showed significantly different global transcriptome patterns. Among other findings, our functional analyses revealed that the fungal species relied on different metabolic pathways and virulence factors to survive the host-imposed stress. These data show that adaptation of species as a response to the host is not a phylogenetic trait, but rather has likely evolved independently as a prerequisite to cause human infections. To ensure their survival, pathogens have to adapt immediately to new environments in their hosts, for example, during the transition from the gut to the bloodstream. Here, we investigated the basis of this adaptation in a group of fungal species which are among the most common causes of hospital-acquired infections, the species. On the basis of a human whole-blood infection model, we studied which genes and processes are active over the course of an infection in both the host and four different pathogens. Remarkably, we found that, while the human host response during the early phase of infection is predominantly uniform, the pathogens pursue largely individual strategies and each one regulates genes involved in largely disparate processes in the blood. Our results reveal that , , , and all have developed individual strategies for survival in the host. This indicates that their pathogenicity in humans has evolved several times independently and that genes which are central for survival in the host for one species may be irrelevant in another.
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http://dx.doi.org/10.1128/mBio.02435-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542370PMC
October 2020

Inflammation-associated suppression of metabolic gene networks in acute and chronic liver disease.

Arch Toxicol 2020 01 9;94(1):205-217. Epub 2020 Jan 9.

IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany.

Inflammation has been recognized as essential for restorative regeneration. Here, we analyzed the sequential processes during onset of liver injury and subsequent regeneration based on time-resolved transcriptional regulatory networks (TRNs) to understand the relationship between inflammation, mature organ function, and regeneration. Genome-wide expression and TRN analysis were performed time dependently in mouse liver after acute injury by CCl (2 h, 8 h, 1, 2, 4, 6, 8, 16 days), as well as lipopolysaccharide (LPS, 24 h) and compared to publicly available data after tunicamycin exposure (mouse, 6 h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatiotemporal investigation differentiated lobular zones for signaling and transcription factor expression. Acute CCl intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24 h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl-induced necrosis, but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48 h. The same upstream regulators (e.g. inhibited RXR function) were implicated in increased inflammation and suppressed metabolism. The concomitant inflammation/metabolism TRN occurred similarly after acute LPS and tunicamycin challenges, in chronic mouse models and also in human liver diseases. Downregulation of metabolic genes occurs concomitantly to induce inflammation-associated genes as an early response and appears to be initiated by similar upstream regulators in acute and chronic liver diseases in humans and mice. In the acute setting, proliferation and restorative regeneration associated TRNs peak only later when metabolism is already suppressed.
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http://dx.doi.org/10.1007/s00204-019-02630-3DOI Listing
January 2020

Increased Expression of RUNX1 in Liver Correlates with NASH Activity Score in Patients with Non-Alcoholic Steatohepatitis (NASH).

Cells 2019 10 18;8(10). Epub 2019 Oct 18.

University Children Hospital (KUNO), University Hospital of Regensburg, 93053 Regensburg, Germany.

Given the important role of angiogenesis in liver pathology, the current study investigated the role of Runt-related transcription factor 1 (RUNX1), a regulator of developmental angiogenesis, in the pathogenesis of non-alcoholic steatohepatitis (NASH). Quantitative RT-PCRs and a transcription factor analysis of angiogenesis-associated differentially expressed genes in liver tissues of healthy controls, patients with steatosis and NASH, indicated a potential role of in NASH. The gene expression of was correlated with histopathological attributes of patients. The protein expression of RUNX1 in liver was studied by immunohistochemistry. To explore the underlying mechanisms, in vitro studies using siRNA and overexpression plasmids were performed in endothelial cells (ECs). RUNX1 expression was significantly correlated with inflammation, fibrosis and NASH activity score in NASH patients. Its expression was conspicuous in liver non-parenchymal cells. In vitro, factors from steatotic hepatocytes and/or VEGF or TGF- significantly induced the expression of in ECs. regulated the expression of angiogenic and adhesion molecules in ECs, including CCL2, PECAM1 and VCAM1, which was shown by silencing or over-expression of . Furthermore, increased the angiogenic activity of ECs. This study reports that steatosis-induced augmented the expression of adhesion and angiogenic molecules and properties in ECs and may be involved in enhancing inflammation and disease severity in NASH.
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http://dx.doi.org/10.3390/cells8101277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830073PMC
October 2019

Publisher Correction: Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly.

Nat Commun 2019 May 31;10(1):2459. Epub 2019 May 31.

Research Group Medical Systems Biology, Institute of Experimental Medicine, Christian-Albrechts-University Kiel, D-24105, Kiel, Germany.

The original version of this Article contained an error in the spelling of the author Jule Müller, which was incorrectly given as Julia Müller. Additionally, in Fig. 4a, the blue-red colour scale for fold change in ageing/disease regulation included a blue stripe in place of a red stripe at the right-hand end of the scale. These errors have been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-10559-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544640PMC
May 2019

DeltaMS: a tool to track isotopologues in GC- and LC-MS data.

Metabolomics 2018 02 27;14(4):41. Epub 2018 Feb 27.

Department of Bioorganic Analytics, Institute for Inorganic and Analytical Chemistry, Friedrich Schiller University Jena,, Lessingstr. 8, 07743, Jena, Germany.

Introduction: Stable isotopic labeling experiments are powerful tools to study metabolic pathways, to follow tracers and fluxes in biotic and abiotic transformations and to elucidate molecules involved in metal complexing.

Objective: To introduce a software tool for the identification of isotopologues from mass spectrometry data.

Methods: DeltaMS relies on XCMS peak detection and XCMS isotopologue grouping and then analyses data for specific isotope ratios and the relative error of these ratios. It provides pipelines for recognition of isotope patterns in three experiment types commonly used in isotopic labeling studies: (1) search for isotope signatures with a specific mass shift and intensity ratio in one sample set, (2) analyze two sample sets for a specific mass shift and, optionally, the isotope ratio, whereby one sample set is isotope-labeled, and one is not, (3) analyze isotope-guided perturbation experiments with a setup described in XCMS.

Results: To illustrate the versatility of DeltaMS, we analyze data sets from case-studies that commonly pose challenges in evaluation of natural isotopes or isotopic signatures in labeling experiment. In these examples, the untargeted detection of sulfur, bromine and artificial metal isotopic patterns is enabled by the automated search for specific isotopes or isotope signatures.

Conclusion: DeltaMS provides a platform for the identification of (pre-defined) isotopologues in MS data from single samples or comparative metabolomics data sets.
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http://dx.doi.org/10.1007/s11306-018-1336-xDOI Listing
February 2018

Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis.

J Hepatol 2019 06 1;70(6):1192-1202. Epub 2019 Feb 1.

Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany. Electronic address:

Background & Aims: The mammalian circadian clock controls various aspects of liver metabolism and integrates nutritional signals. Recently, we described Hedgehog (Hh) signaling as a novel regulator of liver lipid metabolism. Herein, we investigated crosstalk between hepatic Hh signaling and circadian rhythm.

Methods: Diurnal rhythms of Hh signaling were investigated in liver and hepatocytes from mice with ablation of Smoothened (SAC-KO) and crossbreeds with PER2::LUC reporter mice. By using genome-wide screening, qPCR, immunostaining, ELISA and RNAi experiments in vitro we identified relevant transcriptional regulatory steps. Shotgun lipidomics and metabolic cages were used for analysis of metabolic alterations and behavior.

Results: Hh signaling showed diurnal oscillations in liver and hepatocytes in vitro. Correspondingly, the level of Indian Hh, oscillated in serum. Depletion of the clock gene Bmal1 in hepatocytes resulted in significant alterations in the expression of Hh genes. Conversely, SAC-KO mice showed altered expression of clock genes, confirmed by RNAi against Gli1 and Gli3. Genome-wide screening revealed that SAC-KO hepatocytes showed time-dependent alterations in various genes, particularly those associated with lipid metabolism. The clock/hedgehog module further plays a role in rhythmicity of steatosis, and in the response of the liver to a high-fat diet or to differently timed starvation.

Conclusions: For the first time, Hh signaling in hepatocytes was found to be time-of-day dependent and to feed back on the circadian clock. Our findings suggest an integrative role of Hh signaling, mediated mainly by GLI factors, in maintaining homeostasis of hepatic lipid metabolism by balancing the circadian clock.

Lay Summary: The results of our investigation show for the first time that the Hh signaling in hepatocytes is time-of-day dependent, leading to differences not only in transcript levels but also in the amount of Hh ligands in peripheral blood. Conversely, Hh signaling is able to feed back to the circadian clock.
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http://dx.doi.org/10.1016/j.jhep.2019.01.022DOI Listing
June 2019

Comparative Genomics of Serial Isolates and the Rapid Acquisition of Echinocandin Resistance during Therapy.

Antimicrob Agents Chemother 2019 02 29;63(2). Epub 2019 Jan 29.

National Reference Center for Invasive Mycoses, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany

The opportunistic pathogen shows a concerning increase in drug resistance. Here, we present the analysis of two serial bloodstream isolates, obtained 12 days apart. Both isolates show pan-azole resistance and echinocandin resistance was acquired during the sampling interval. Genome sequencing identified nine nonsynonymous SNVs between the strains, including a S663P substitution in FKS2 and previously undescribed SNVs in and , offering insight into how acquires drug resistance and adapts to a human host.
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http://dx.doi.org/10.1128/AAC.01628-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355595PMC
February 2019

Impairing L-Threonine Catabolism Promotes Healthspan through Methylglyoxal-Mediated Proteohormesis.

Cell Metab 2018 04 15;27(4):914-925.e5. Epub 2018 Mar 15.

Energy Metabolism Laboratory, Institute of Translational Medicine, D-HEST, Swiss Federal Institute of Technology (ETH) Zürich, Schwerzenbach 8603, Switzerland. Electronic address:

Whether and how regulation of genes and pathways contributes to physiological aging is topic of intense scientific debate. By performing an RNA expression-based screen for genes downregulated during aging of three different species, we identified glycine-C-acetyltransferase (GCAT, EC 2.3.1.29). Impairing gcat expression promotes the lifespan of C. elegans by interfering with threonine catabolism to promote methylglyoxal (MGO; CAS 78-98-8) formation in an amine oxidase-dependent manner. MGO is a reactive dicarbonyl inducing diabetic complications in mammals by causing oxidative stress and damaging cellular components, including proteins. While high concentrations of MGO consistently exert toxicity in nematodes, we unexpectedly find that low-dose MGO promotes lifespan, resembling key mediators of gcat impairment. These were executed by the ubiquitin-proteasome system, namely PBS-3 and RPN-6.1 subunits, regulated by the stress-responsive transcriptional regulators SKN-1/NRF2 and HSF-1. Taken together, GCAT acts as an evolutionary conserved aging-related gene by orchestrating an unexpected nonlinear impact of proteotoxic MGO on longevity.
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http://dx.doi.org/10.1016/j.cmet.2018.02.004DOI Listing
April 2018

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

Mol Cell Proteomics 2018 06 5;17(6):1084-1096. Epub 2018 Mar 5.

From the ‡Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI), Jena, Germany;

Invasive infections by the human pathogenic fungus 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, 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 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 proteins that were differentially abundant in the phagolysosome. 472 of the host proteins were overrepresented in the mutant and 165 in the wt conidia-containing phagolysosome. Eight of the fungal proteins were produced only in 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 conidia-containing phagolysosomes and a potent bioinformatics algorithm, we were able to confirm conidia-dependent modification of phagolysosomal processes that have been described before and beyond that, identify pathways that have not been implicated in evasion strategy, yet.Mass spectrometry proteomics data are available ProteomeXchange with identifiers PXD005724 and PXD006134.
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http://dx.doi.org/10.1074/mcp.RA117.000069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986250PMC
June 2018

Interaction Causes Changes in Gene Expression Profiles and Jasmonate Levels on Different Time Scales.

Front Microbiol 2018 13;9:217. Epub 2018 Feb 13.

Department of Plant Physiology, Matthias Schleiden Institute of Genetics, Bioinformatics and Molecular Botany, Friedrich-Schiller-University Jena, Jena, Germany.

is a soil-borne vascular pathogen that causes severe wilt symptoms in a wide range of plants. Co-culture of the fungus with roots for 24 h induces many changes in the gene expression profiles of both partners, even before defense-related phytohormone levels are induced in the plant. Both partners reprogram sugar and amino acid metabolism, activate genes for signal perception and transduction, and induce defense- and stress-responsive genes. Furthermore, analysis of expression profiles suggests a redirection from growth to defense. After 3 weeks, severe disease symptoms can be detected for wild-type plants while mutants impaired in jasmonate synthesis and perception perform much better. Thus, plant jasmonates have an important influence on the interaction, which is already visible at the mRNA level before hormone changes occur. The plant and fungal genes that rapidly respond to the presence of the partner might be crucial for early recognition steps and the future development of the interaction. Thus they are potential targets for the control of -induced wilt diseases.
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http://dx.doi.org/10.3389/fmicb.2018.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819561PMC
February 2018

Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly.

Nat Commun 2018 01 30;9(1):327. Epub 2018 Jan 30.

Research Group Medical Systems Biology, Institute of Experimental Medicine, Christian-Albrechts-University Kiel, D-24105, Kiel, Germany.

Disease epidemiology during ageing shows a transition from cancer to degenerative chronic disorders as dominant contributors to mortality in the old. Nevertheless, it has remained unclear to what extent molecular signatures of ageing reflect this phenomenon. Here we report on the identification of a conserved transcriptomic signature of ageing based on gene expression data from four vertebrate species across four tissues. We find that ageing-associated transcriptomic changes follow trajectories similar to the transcriptional alterations observed in degenerative ageing diseases but are in opposite direction to the transcriptomic alterations observed in cancer. We confirm the existence of a similar antagonism on the genomic level, where a majority of shared risk alleles which increase the risk of cancer decrease the risk of chronic degenerative disorders and vice versa. These results reveal a fundamental trade-off between cancer and degenerative ageing diseases that sheds light on the pronounced shift in their epidemiology during ageing.
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http://dx.doi.org/10.1038/s41467-017-02395-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790807PMC
January 2018

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

Sci Rep 2018 01 11;8(1):433. Epub 2018 Jan 11.

Friedrich-Schiller-University, Department of Bioinformatics, Jena, 07743, Germany.

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).
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http://dx.doi.org/10.1038/s41598-017-18370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764996PMC
January 2018

Differential regulation of the transcriptomic and secretomic landscape of sensor and effector functions of human airway epithelial cells.

Mucosal Immunol 2018 05 3;11(3):627-642. Epub 2018 Jan 3.

Septomics Research Centre, Jena University Hospital, Jena, Germany.

Protein secretion upon TLR, TNFR1, and IFNGR ligation in the human airways is considered to be central for the orchestration of pulmonary inflammatory and immune responses. In this study, we compared the gene expression and protein secretion profiles in response to specific stimulation of all expressed TLRs and in further comparison to TNFR1 and IFNGR in primary human airway epithelial cells. In addition to 22 cytokines, we observed the receptor-induced regulation of 571 genes and 1,012 secreted proteins. Further analysis revealed high similarities between the transcriptional TLR sensor and TNFR1 effector responses. However, secretome to transcriptome comparisons showed a broad receptor stimulation-dependent release of proteins that were not transcriptionally regulated. Many of these proteins are annotated to exosomes with associations to, for example, antigen presentation and wound-healing, or were identified as secretable proteins related to immune responses. Thus, we show a hitherto unrecognized scope of receptor-induced responses in airway epithelium, involving several additional functions for the immune response, exosomal communication and tissue homeostasis.
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http://dx.doi.org/10.1038/mi.2017.100DOI Listing
May 2018

Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake.

J R Soc Interface 2017 08;14(133)

Department of Bioinformatics, Friedrich-Schiller-University Jena, Jena, Germany.

Intrinsic of non-alcoholic fatty liver diseases is an aberrant accumulation of triglycerides (steatosis), which occurs inhomogeneously within lobules. To improve our understanding of the mechanisms involved in this zonation patterning, we developed a mathematical multicompartment model of hepatic fatty acid metabolism accompanied by blood flow simulations. A model analysis determines the influence of the uptake process of fatty acids, the porto-central gradient of plasma fatty acid concentration, and the oxygen supply via blood on the zonation of triglyceride accumulation. From this theoretical perspective, the plasma oxygen gradient, but not the fatty acid gradient, leads the way to a zonated triglyceride accumulation by its decisive role in oxidative processes. In addition, the uptake mechanism of fatty acids seems to be fundamental for a pericentral dominance of steatosis. However, the mechanism of cellular fatty acid uptake from the blood is still under debate. Our theoretical approach supports the transporter-mediated uptake mechanism and reveals that the maximal velocity of fatty acid uptake affects the switching between a periportal and a pericentral triglyceride accumulation. Further research on hepatic fatty acid uptake is needed to push forward our understanding of aberrant triglyceride accumulation in diet-induced steatosis.
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http://dx.doi.org/10.1098/rsif.2017.0443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582132PMC
August 2017

Global analysis of glycoproteins identifies markers of endotoxin tolerant monocytes and GPR84 as a modulator of TNFα expression.

Sci Rep 2017 04 12;7(1):838. Epub 2017 Apr 12.

Septomics Research Center, Jena University Hospital, Jena, Germany.

Exposure of human monocytes to lipopolysaccharide (LPS) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance. In this study, we investigated the LPS-induced global glycoprotein expression changes of tolerant human monocytes and THP-1 cells to identify markers and glycoprotein targets capable to modulate the immunosuppressive state. Using hydrazide chemistry and LC-MS/MS analysis, we analyzed glycoprotein expression changes during a 48 h LPS time course. The cellular snapshots at different time points identified 1491 glycoproteins expressed by monocytes and THP-1 cells. Label-free quantitative analysis revealed transient or long-lasting LPS-induced expression changes of secreted or membrane-anchored glycoproteins derived from intracellular membrane coated organelles or from the plasma membrane. Monocytes and THP-1 cells demonstrated marked differences in glycoproteins differentially expressed in the tolerant state. Among the shared differentially expressed glycoproteins G protein-coupled receptor 84 (GPR84) was identified as being capable of modulating pro-inflammatory TNFα mRNA expression in the tolerant cell state when activated with its ligand Decanoic acid.
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http://dx.doi.org/10.1038/s41598-017-00828-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429802PMC
April 2017

Specific and Novel microRNAs Are Regulated as Response to Fungal Infection in Human Dendritic Cells.

Front Microbiol 2017 23;8:270. Epub 2017 Feb 23.

Systems Biology/Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute Jena, Germany.

Within the last two decades, the incidence of invasive fungal infections has been significantly increased. They are characterized by high mortality rates and are often caused by and . The increasing number of infections underlines the necessity for additional anti-fungal therapies, which require extended knowledge of gene regulations during fungal infection. MicroRNAs are regulators of important cellular processes, including the immune response. By analyzing their regulation and impact on target genes, novel therapeutic and diagnostic approaches may be developed. Here, we examine the role of microRNAs in human dendritic cells during fungal infection. Dendritic cells represent the bridge between the innate and the adaptive immune systems. Therefore, analysis of gene regulation of dendritic cells is of particular significance. By applying next-generation sequencing of small RNAs, we quantify microRNA expression in monocyte-derived dendritic cells after 6 and 12 h of infection with and as well as treatment with lipopolysaccharides (LPS). We identified 26 microRNAs that are differentially regulated after infection by the fungi or LPS. Three and five of them are specific for fungal infections after 6 and 12 h, respectively. We further validated interactions of miR-132-5p and miR-212-5p with immunological relevant target genes, such as , and , on both RNA and protein level. Our results indicate that these microRNAs fine-tune the expression of immune-related target genes during fungal infection. Beyond that, we identified previously undiscovered microRNAs. We validated three novel microRNAs via qRT-PCR. A comparison with known microRNAs revealed possible relations with the miR-378 family and miR-1260a/b for two of them, while the third one features a unique sequence with no resemblance to known microRNAs. In summary, this study analyzes the effect of known microRNAs in dendritic cells during fungal infections and proposes novel microRNAs that could be experimentally verified.
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http://dx.doi.org/10.3389/fmicb.2017.00270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322194PMC
February 2017

Discovery of an Extended Austinoid Biosynthetic Pathway in Aspergillus calidoustus.

ACS Chem Biol 2017 05 15;12(5):1227-1234. Epub 2017 Mar 15.

Friedrich Schiller University , 07745 Jena, Germany.

Filamentous fungi produce a wide range of natural products that are commonly used in various industrial contexts (e.g., pharmaceuticals and insecticides). Meroterpenoids are natural products of interest because of their various biological activities. Among the meroterpenoids, there is a group of insecticidal compounds known as the austinoids. These compounds have also been studied because of their intriguing spiro-lactone ring formation along with various modifications. Here, we present an extension of the original austinol/dehydroaustinol biosynthesis pathway from Aspergillus nidulans in the recently identified filamentous fungus Aspergillus calidoustus. Besides the discovery and elucidation of further derivatives, genome mining led to the discovery of new putative biosynthetic genes. The genes involved in the biosynthesis of later austinoid products were characterized, and among them was a second polyketide synthase gene in the A. calidoustus cluster that was unusual because it was a noninterative polyketide synthase producing a diketide. This diketide product was then loaded onto the austinoid backbone, resulting in a new insecticidal derivative, calidodehydroaustin.
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http://dx.doi.org/10.1021/acschembio.7b00003DOI Listing
May 2017

Global Transcriptional Response of Human Liver Cells to Ethanol Stress of Different Strength Reveals Hormetic Behavior.

Alcohol Clin Exp Res 2017 May 27;41(5):883-894. Epub 2017 Mar 27.

Bioreactor Group , Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: The liver is the major site for alcohol metabolism in the body and therefore the primary target organ for ethanol (EtOH)-induced toxicity. In this study, we investigated the in vitro response of human liver cells to different EtOH concentrations in a perfused bioartificial liver device that mimics the complex architecture of the natural organ.

Methods: Primary human liver cells were cultured in the bioartificial liver device and treated for 24 hours with medium containing 150 mM (low), 300 mM (medium), or 600 mM (high) EtOH, while a control culture was kept untreated. Gene expression patterns for each EtOH concentration were monitored using Affymetrix Human Gene 1.0 ST Gene chips. Scaled expression profiles of differentially expressed genes (DEGs) were clustered using Fuzzy c-means algorithm. In addition, functional classification methods, KEGG pathway mapping and also a machine learning approach (Random Forest) were utilized.

Results: A number of 966 (150 mM EtOH), 1,334 (300 mM EtOH), or 4,132 (600 mM EtOH) genes were found to be differentially expressed. Dose-response relationships of the identified clusters of co-expressed genes showed a monotonic, threshold, or nonmonotonic (hormetic) behavior. Functional classification of DEGs revealed that low or medium EtOH concentrations operate adaptation processes, while alterations observed for the high EtOH concentration reflect the response to cellular damage. The genes displaying a hormetic response were functionally characterized by overrepresented "cellular ketone metabolism" and "carboxylic acid metabolism." Altered expression of the genes BAHD1 and H3F3B was identified as sufficient to classify the samples according to the applied EtOH doses.

Conclusions: Different pathways of metabolic and epigenetic regulation are affected by EtOH exposition and partly undergo hormetic regulation in the bioartificial liver device. Gene expression changes observed at high EtOH concentrations reflect in some aspects the situation of alcoholic hepatitis in humans.
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http://dx.doi.org/10.1111/acer.13361DOI Listing
May 2017

Differential Biphasic Transcriptional Host Response Associated with Coevolution of Hemagglutinin Quasispecies of Influenza A Virus.

Front Microbiol 2016 3;7:1167. Epub 2016 Aug 3.

Department of Virology and Antiviral Therapy, Jena University Hospital Jena, Germany.

Severe influenza associated with strong symptoms and lung inflammation can be caused by intra-host evolution of quasispecies with aspartic acid or glycine in hemagglutinin position 222 (HA-222D/G; H1 numbering). To gain insights into the dynamics of host response to this coevolution and to identify key mechanisms contributing to copathogenesis, the lung transcriptional response of BALB/c mice infected with an A(H1N1)pdm09 isolate consisting HA-222D/G quasispecies was analyzed from days 1 to 12 post infection (p.i). At day 2 p.i. 968 differentially expressed genes (DEGs) were detected. The DEG number declined to 359 at day 4 and reached 1001 at day 7 p.i. prior to recovery. Interestingly, a biphasic expression profile was shown for the majority of these genes. Cytokine assays confirmed these results on protein level exemplarily for two key inflammatory cytokines, interferon gamma and interleukin 6. Using a reverse engineering strategy, a regulatory network was inferred to hypothetically explain the biphasic pattern for selected DEGs. Known regulatory interactions were extracted by Pathway Studio 9.0 and integrated during network inference. The hypothetic gene regulatory network revealed a positive feedback loop of Ifng, Stat1, and Tlr3 gene signaling that was triggered by the HA-G222 variant and correlated with a clinical symptom score indicating disease severity.
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http://dx.doi.org/10.3389/fmicb.2016.01167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971777PMC
August 2016

Conserved genes and pathways in primary human fibroblast strains undergoing replicative and radiation induced senescence.

Biol Res 2016 Jul 28;49(1):34. Epub 2016 Jul 28.

Leibniz Institute for Age Research-Fritz Lipmann Institute e.V. (FLI), Beutenbergstrasse 11, 07745, Jena, Germany.

Background: Cellular senescence is induced either internally, for example by replication exhaustion and cell division, or externally, for example by irradiation. In both cases, cellular damages accumulate which, if not successfully repaired, can result in senescence induction. Recently, we determined the transcriptional changes combined with the transition into replicative senescence in primary human fibroblast strains. Here, by γ-irradiation we induced premature cellular senescence in the fibroblast cell strains (HFF and MRC-5) and determined the corresponding transcriptional changes by high-throughput RNA sequencing.

Results: Comparing the transcriptomes, we found a high degree of similarity in differential gene expression in replicative as well as in irradiation induced senescence for both cell strains suggesting, in each cell strain, a common cellular response to error accumulation. On the functional pathway level, "Cell cycle" was the only pathway commonly down-regulated in replicative and irradiation-induced senescence in both fibroblast strains, confirming the tight link between DNA repair and cell cycle regulation. However, "DNA repair" and "replication" pathways were down-regulated more strongly in fibroblasts undergoing replicative exhaustion. We also retrieved genes and pathways in each of the cell strains specific for irradiation induced senescence.

Conclusion: We found the pathways associated with "DNA repair" and "replication" less stringently regulated in irradiation induced compared to replicative senescence. The strong regulation of these pathways in replicative senescence highlights the importance of replication errors for its induction.
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http://dx.doi.org/10.1186/s40659-016-0095-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963952PMC
July 2016

Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue.

Arch Toxicol 2016 Oct 23;90(10):2513-29. Epub 2016 Jun 23.

Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

It is well known that isolation and cultivation of primary hepatocytes cause major gene expression alterations. In the present genome-wide, time-resolved study of cultivated human and mouse hepatocytes, we made the observation that expression changes in culture strongly resemble alterations in liver diseases. Hepatocytes of both species were cultivated in collagen sandwich and in monolayer conditions. Genome-wide data were also obtained from human NAFLD, cirrhosis, HCC and hepatitis B virus-infected tissue as well as mouse livers after partial hepatectomy, CCl4 intoxication, obesity, HCC and LPS. A strong similarity between cultivation and disease-induced expression alterations was observed. For example, expression changes in hepatocytes induced by 1-day cultivation and 1-day CCl4 exposure in vivo correlated with R = 0.615 (p < 0.001). Interspecies comparison identified predominantly similar responses in human and mouse hepatocytes but also a set of genes that responded differently. Unsupervised clustering of altered genes identified three main clusters: (1) downregulated genes corresponding to mature liver functions, (2) upregulation of an inflammation/RNA processing cluster and (3) upregulated migration/cell cycle-associated genes. Gene regulatory network analysis highlights overrepresented and deregulated HNF4 and CAR (Cluster 1), Krüppel-like factors MafF and ELK1 (Cluster 2) as well as ETF (Cluster 3) among the interspecies conserved key regulators of expression changes. Interventions ameliorating but not abrogating cultivation-induced responses include removal of non-parenchymal cells, generation of the hepatocytes' own matrix in spheroids, supplementation with bile salts and siRNA-mediated suppression of key transcription factors. In conclusion, this study shows that gene regulatory network alterations of cultivated hepatocytes resemble those of inflammatory liver diseases and should therefore be considered and exploited as disease models.
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http://dx.doi.org/10.1007/s00204-016-1761-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043005PMC
October 2016

Data-based Reconstruction of Gene Regulatory Networks of Fungal Pathogens.

Front Microbiol 2016 22;7:570. Epub 2016 Apr 22.

Research Group Systems Biology and Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena, Germany.

In the emerging field of systems biology of fungal infection, one of the central roles belongs to the modeling of gene regulatory networks (GRNs). Utilizing omics-data, GRNs can be predicted by mathematical modeling. Here, we review current advances of data-based reconstruction of both small-scale and large-scale GRNs for human pathogenic fungi. The advantage of large-scale genome-wide modeling is the possibility to predict central (hub) genes and thereby indicate potential biomarkers and drug targets. In contrast, small-scale GRN models provide hypotheses on the mode of gene regulatory interactions, which have to be validated experimentally. Due to the lack of sufficient quantity and quality of both experimental data and prior knowledge about regulator-target gene relations, the genome-wide modeling still remains problematic for fungal pathogens. While a first genome-wide GRN model has already been published for Candida albicans, the feasibility of such modeling for Aspergillus fumigatus is evaluated in the present article. Based on this evaluation, opinions are drawn on future directions of GRN modeling of fungal pathogens. The crucial point of genome-wide GRN modeling is the experimental evidence, both used for inferring the networks (omics 'first-hand' data as well as literature data used as prior knowledge) and for validation and evaluation of the inferred network models.
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http://dx.doi.org/10.3389/fmicb.2016.00570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840211PMC
May 2016

Longitudinal RNA-Seq Analysis of Vertebrate Aging Identifies Mitochondrial Complex I as a Small-Molecule-Sensitive Modifier of Lifespan.

Cell Syst 2016 02 24;2(2):122-32. Epub 2016 Feb 24.

Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745 Jena, Germany; Scuola Normale Superiore, Laboratory of Biology, c/o Istituto di Biofisica del CNR, via Moruzzi 1, 56124 Pisa, Italy. Electronic address:

Mutations and genetic variability affect gene expression and lifespan, but the impact of variations in gene expression within individuals on their aging-related mortality is poorly understood. We performed a longitudinal study in the short-lived killifish, Nothobranchius furzeri, and correlated quantitative variations in gene expression during early adult life with lifespan. Shorter- and longer-lived individuals differ in their gene expression before the onset of aging-related mortality; differences in gene expression are more pronounced early in life. We identified mitochondrial respiratory chain complex I as a hub in a module of genes whose expression is negatively correlated with lifespan. Accordingly, partial pharmacological inhibition of complex I by the small molecule rotenone reversed aging-related regulation of gene expression and extended lifespan in N. furzeri by 15%. These results support the use of N. furzeri as a vertebrate model for identifying the protein targets, pharmacological modulators, and individual-to-individual variability associated with aging.
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http://dx.doi.org/10.1016/j.cels.2016.01.014DOI Listing
February 2016

How to Predict Molecular Interactions between Species?

Front Microbiol 2016 31;7:442. Epub 2016 Mar 31.

Research Group Systems Biology and Bioinformatics, Leibniz-Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute Jena, Germany.

Organisms constantly interact with other species through physical contact which leads to changes on the molecular level, for example the transcriptome. These changes can be monitored for all genes, with the help of high-throughput experiments such as RNA-seq or microarrays. The adaptation of the gene expression to environmental changes within cells is mediated through complex gene regulatory networks. Often, our knowledge of these networks is incomplete. Network inference predicts gene regulatory interactions based on transcriptome data. An emerging application of high-throughput transcriptome studies are dual transcriptomics experiments. Here, the transcriptome of two or more interacting species is measured simultaneously. Based on a dual RNA-seq data set of murine dendritic cells infected with the fungal pathogen Candida albicans, the software tool NetGenerator was applied to predict an inter-species gene regulatory network. To promote further investigations of molecular inter-species interactions, we recently discussed dual RNA-seq experiments for host-pathogen interactions and extended the applied tool NetGenerator (Schulze et al., 2015). The updated version of NetGenerator makes use of measurement variances in the algorithmic procedure and accepts gene expression time series data with missing values. Additionally, we tested multiple modeling scenarios regarding the stimuli functions of the gene regulatory network. Here, we summarize the work by Schulze et al. (2015) and put it into a broader context. We review various studies making use of the dual transcriptomics approach to investigate the molecular basis of interacting species. Besides the application to host-pathogen interactions, dual transcriptomics data are also utilized to study mutualistic and commensalistic interactions. Furthermore, we give a short introduction into additional approaches for the prediction of gene regulatory networks and discuss their application to dual transcriptomics data. We conclude that the application of network inference on dual-transcriptomics data is a promising approach to predict molecular inter-species interactions.
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http://dx.doi.org/10.3389/fmicb.2016.00442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814556PMC
April 2016

Genome-Wide Expression Profiling Reveals S100B as Biomarker for Invasive Aspergillosis.

Front Microbiol 2016 21;7:320. Epub 2016 Mar 21.

University Hospital Würzburg, Medical Hospital II Würzburg, Germany.

Invasive aspergillosis (IA) is a devastating opportunistic infection and its treatment constitutes a considerable burden for the health care system. Immunocompromised patients are at an increased risk for IA, which is mainly caused by the species Aspergillus fumigatus. An early and reliable diagnosis is required to initiate the appropriate antifungal therapy. However, diagnostic sensitivity and accuracy still needs to be improved, which can be achieved at least partly by the definition of new biomarkers. Besides the direct detection of the pathogen by the current diagnostic methods, the analysis of the host response is a promising strategy toward this aim. Following this approach, we sought to identify new biomarkers for IA. For this purpose, we analyzed gene expression profiles of hematological patients and compared profiles of patients suffering from IA with non-IA patients. Based on microarray data, we applied a comprehensive feature selection using a random forest classifier. We identified the transcript coding for the S100 calcium-binding protein B (S100B) as a potential new biomarker for the diagnosis of IA. Considering the expression of this gene, we were able to classify samples from patients with IA with 82.3% sensitivity and 74.6% specificity. Moreover, we validated the expression of S100B in a real-time reverse transcription polymerase chain reaction (RT-PCR) assay and we also found a down-regulation of S100B in A. fumigatus stimulated DCs. An influence on the IL1B and CXCL1 downstream levels was demonstrated by this S100B knockdown. In conclusion, this study covers an effective feature selection revealing a key regulator of the human immune response during IA. S100B may represent an additional diagnostic marker that in combination with the established techniques may improve the accuracy of IA diagnosis.
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http://dx.doi.org/10.3389/fmicb.2016.00320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800190PMC
April 2016

Proteomic Profiling of Serological Responses to Aspergillus fumigatus Antigens in Patients with Invasive Aspergillosis.

J Proteome Res 2016 05 24;15(5):1580-91. Epub 2016 Mar 24.

Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute (HKI) , 07745 Jena, Germany.

Aspergillus fumigatus is the species that most commonly causes the opportunistic infection invasive aspergillosis (IA) in patients being treated for hematological malignancies. Little is known about the A. fumigatus proteins that trigger the production of Aspergillus-specific IgG antibodies during the course of IA. To characterize the serological response to A. fumigatus protein antigens, mycelial proteins were separated by 2-D gel electrophoresis. The gels were immunoblotted with sera from patients with probable and proven IA and control patients without IA. We identified 49 different fungal proteins, which gave a positive IgG antibody signal. Most of these antigens play a role in primary metabolism and stress responses. Overall, our analysis identified 18 novel protein antigens from A. fumigatus. To determine whether these antigens can be used as diagnostic or prognostic markers or exhibit a protective activity, we employed supervised machine learning with decision trees. We identified two candidates for further analysis, the protein antigens CpcB and Shm2. Heterologously produced Shm2 induced a strongly proinflammatory response in human peripheral blood mononuclear cells after in vitro stimulation. In contrast, CpcB did not activate the immune response of PBMCs. These findings could serve as the basis for the development of an immunotherapy of IA.
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http://dx.doi.org/10.1021/acs.jproteome.6b00042DOI Listing
May 2016

Draft Genome Sequences of Fungus Aspergillus calidoustus.

Genome Announc 2016 Mar 10;4(2). Epub 2016 Mar 10.

Leibniz Junior Research Group-Biobricks of Microbial Natural Product Syntheses, HKI, Jena, Germany

Here, we report the draft genome sequence of Aspergillus calidoustus (strain SF006504). The functional annotation of A. calidoustus predicts a relatively large number of secondary metabolite gene clusters. The presented genome sequence builds the basis for further genome mining.
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http://dx.doi.org/10.1128/genomeA.00102-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786660PMC
March 2016

Editorial: Computational Systems Biology of Pathogen-Host Interactions.

Front Microbiol 2016 4;7:21. Epub 2016 Feb 4.

Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute Jena, Germany.

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http://dx.doi.org/10.3389/fmicb.2016.00021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740391PMC
February 2016

Facing the challenges of multiscale modelling of bacterial and fungal pathogen-host interactions.

Brief Funct Genomics 2017 03;16(2):57-69

Leibniz-Institute for Natural Product Research and Infection Biology-Hans-Knoell-Institute, Jena, Germany.

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.
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http://dx.doi.org/10.1093/bfgp/elv064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439285PMC
March 2017

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

Cell Microbiol 2016 07 26;18(7):889-904. Epub 2016 Feb 26.

Septomics Research Centre, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany.

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-κB and MAPK signalling pathways in the response to infection. Hence, we inferred a gene regulatory network based on differentially expressed NF-κB and MAPK pathway components and their predicted transcriptional targets. The network model predicted activation of GDF15 by NF-κB was experimentally validated. Furthermore, inhibition of NF-κB activation in C. albicans infected C2BBe1 cells led to enhanced cytotoxicity in the epithelial cells. Taken together our study identifies NF-κB activation as an important protective signalling pathway in the response of epithelial cells to C. albicans.
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http://dx.doi.org/10.1111/cmi.12566DOI Listing
July 2016