Publications by authors named "Bernd Schmeck"

101 Publications

Tribolium castaneum defensin 1 kills Moraxella catarrhalisin an in vitro infection model but does not harm commensal bacteria.

Virulence 2021 Dec;12(1):1003-1010

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Marburg, Germany.

is a bacterial pathogen that causes respiratory tract infections in humans. The increasing prevalence of antibiotic-resistant strains has created a demand for alternative treatment options. We therefore tested 23 insect antimicrobial peptides (AMPs) for their activity against in a human infection model with primary macrophages, and against commensal bacteria. Effects on bacterial growth were determined by colony counting and growth curve analysis. The inflammatory macrophage response was characterized by qPCR and multiplex ELISA. Eleven of the AMPs were active against . Defensin 1 from the red flour beetle significantly inhibited bacterial growth and reduced the number of colony forming units. This AMP also showed antibacterial activity in the infection model, reducing cytokine expression and release by macrophages. Defensin 1 had no effect on the commensal bacteria and . However, sarcotoxin 1 C from the green bottle fly was active against and , but not against . The ability of defensin 1 to inhibit but not selected commensal bacteria, and the absence of cytotoxic or inflammatory effects against human blood-derived macrophages, suggests this AMP may be suitable for development as a new therapeutic lead against antibiotic-resistant .
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http://dx.doi.org/10.1080/21505594.2021.1908741DOI Listing
December 2021

[Role of genetic factors in pneumonia and COVID-19].

Pneumologe (Berl) 2021 Mar 5:1-5. Epub 2021 Mar 5.

Institut für Lungenforschung, Universities of Gießen and Marburg Lung Center (UGMLC), Philipps-Universität Marburg, Hans-Meerwein-Str. 2, 35043 Marburg, Deutschland.

Pneumonia causes the highest mortality of all infectious diseases worldwide. The most common pathogens are bacteria but there are also epidemic or pandemic lung infections caused by influenza or coronaviruses, such as the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the occurrence of antibiotic resistance and immune pathologies, such as in sepsis, important challenges lie in considering the susceptibility of individual patients. Here, age, medication and comorbidities are considered; however, there is also clear evidence of genetic influences on the individual risk of developing pneumonia or developing a severe course of the disease. This article discusses the genetic influences on pneumonia and the clinical significance.
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http://dx.doi.org/10.1007/s10405-021-00385-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934978PMC
March 2021

Pro- and Antitumorigenic Capacity of Immunoproteasomes in Shaping the Tumor Microenvironment.

Cancer Immunol Res 2021 Mar 11. Epub 2021 Mar 11.

Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany.

Apart from the constitutive proteasome, the immunoproteasome that comprises the three proteolytic subunits LMP2, MECL-1, and LMP7 is expressed in most immune cells. In this study, we describe opposing roles for immunoproteasomes in regulating the tumor microenvironment (TME). During chronic inflammation, immunoproteasomes modulated the expression of protumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells, thus triggering the onset of colitis-associated carcinogenesis (CAC) in wild-type mice. Consequently, immunoproteasome-deficient animals (LMP2/MECL-1/LMP7-null mice) were almost completely resistant to CAC development. In patients with ulcerative colitis with high risk for CAC, immunoproteasome-induced protumorigenic mediators were upregulated. In melanoma tumors, the role of immunoproteasomes is relatively unknown. We found that high expression of immunoproteasomes in human melanoma was associated with better prognosis. Similarly, our data revealed that the immunoproteasome has antitumorigenic activity in a mouse model of melanoma. The antitumor immunity against melanoma was compromised in immunoproteasome-deficient mice because of the impaired activity of CD8 CTLs, CD4 Th1 cells, and antigen-presenting cells. These findings show that immunoproteasomes may exert opposing roles with either pro- or antitumoral properties in a context-dependent manner.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0492DOI Listing
March 2021

Efficient antisense inhibition reveals microRNA-155 to restrain a late-myeloid inflammatory programme in primary human phagocytes.

RNA Biol 2021 Feb 23:1-15. Epub 2021 Feb 23.

Department of Medicine, Institute for Lung Research, Philipps University Marburg, Marburg, Germany.

A persisting obstacle in human immunology is that blood-derived leukocytes are notoriously difficult to manipulate at the RNA level. Therefore, our knowledge about immune-regulatory RNA-networks is largely based on tumour cell-line and rodent knockout models, which do not fully mimic human leukocyte biology. Here, we exploit straightforward cell penetrating peptide (CPP) chemistry to enable efficient loss-of-function phenotyping of regulatory RNAs in primary human blood-derived cells. The classical CPP octaarginine (R8) enabled antisense peptide-nucleic-acid (PNA) oligomer delivery into nearly 100% of human blood-derived macrophages without apparent cytotoxicity even up to micromolar concentrations. In a proof-of-principle experiment, we successfully de-repressed the global microRNA-155 regulome in primary human macrophages using a PNA-R8 oligomer, which phenocopies a CRISPR-Cas9 induced gene knockout. Interestingly, although it is often believed that fairly high concentrations (μM) are needed to achieve antisense activity, our PNA-R8 was effective at 200 nM. RNA-seq characterized microRNA-155 as a broad-acting riboregulator, feedback restraining a late myeloid differentiation-induced pro-inflammatory network, comprising MyD88-signalling and ubiquitin-proteasome components. Our results highlight the important role of the microRNA machinery in fine-control of blood-derived human phagocyte immunity and open the door for further studies on regulatory RNAs in difficult-to-transfect primary human immune cells.
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http://dx.doi.org/10.1080/15476286.2021.1885209DOI Listing
February 2021

Transcriptional analysis identifies potential biomarkers and molecular regulators in acute malaria infection.

Life Sci 2021 Apr 2;270:119158. Epub 2021 Feb 2.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-Universität Marburg, Marburg, Germany; Department of Internal Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, German Center for Lung Research (DZL), Marburg, Germany; German Center for Lung Research (DZL), German Center for infectious Disease Research (DZIF), Center for Synthetic Microbiology (Synmikro), Philipps-Universität Marburg, Germany. Electronic address:

Aims: Malaria is a serious health threat in tropical countries. The causative parasite of Malaria tropica, the severe form, is the protozoan Plasmodium falciparum. In humans, it infects red blood cells, compromising blood flow and tissue perfusion. This study aims to identify potential biomarkers and RNA networks in leukocyte transcriptomes from patients suffering from Malaria tropica.

Materials And Methods: We identified differentially regulated mRNAs and microRNAs in peripheral blood leukocytes of healthy donors and Malaria patients. Genes whose expression changes were not attributable to changes in leukocyte composition were used for bioinformatics analysis and network construction. Using a previously published cohort of community-acquired pneumonia (CAP) patients, we established discriminating transcriptomic features versus Malaria. We aimed to establish differences between the patient groups by principal component (PCA) and receiving operator characteristic (ROC) analyses and in silico cell type deconvolution.

Key Findings: We found 870 genes that were significantly differentially expressed between healthy donors and Malaria patients. E2F1, BIRC5 and CCNB1 were identified to be primarily responsible for PCA separation of these two groups. We searched for biological function and found that cell cycle processes were strongly activated. By in silico cell type deconvolution, we attribute this to an expansion of γδ T cells. Additional discrimination between CAP and Malaria yielded 445 differentially expressed genes, among which immune proteasome transcripts PSMB8, PSMB9 and PSMB10 were significantly induced in Malaria.

Significance: We identified transcripts from patient leukocytes that differentiate between healthy, Malaria and CAP, and indicate a biological context with potential pathophysiological relevance.
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http://dx.doi.org/10.1016/j.lfs.2021.119158DOI Listing
April 2021

Disease-Causing Mutations and Rearrangements in Long Non-coding RNA Gene Loci.

Front Genet 2020 30;11:527484. Epub 2020 Nov 30.

Institute for Lung Research, Philipps University Marburg, Marburg, Germany.

The classic understanding of molecular disease-mechanisms is largely based on protein-centric models. During the past decade however, genetic studies have identified numerous disease-loci in the human genome that do not encode proteins. Such non-coding DNA variants increasingly gain attention in diagnostics and personalized medicine. Of particular interest are long non-coding RNA (lncRNA) genes, which generate transcripts longer than 200 nucleotides that are not translated into proteins. While most of the estimated ~20,000 lncRNAs currently remain of unknown function, a growing number of genetic studies link lncRNA gene aberrations with the development of human diseases, including diabetes, AIDS, inflammatory bowel disease, or cancer. This suggests that the protein-centric view of human diseases does not capture the full complexity of molecular patho-mechanisms, with important consequences for molecular diagnostics and therapy. This review illustrates well-documented lncRNA gene aberrations causatively linked to human diseases and discusses potential lessons for molecular disease models, diagnostics, and therapy.
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http://dx.doi.org/10.3389/fgene.2020.527484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735109PMC
November 2020

p38 and Casein Kinase 2 Mediate Ribonuclease 1 Repression in Inflamed Human Endothelial Cells via Promoter Remodeling Through Nucleosome Remodeling and Deacetylase Complex.

Front Cell Dev Biol 2020 15;8:563604. Epub 2020 Oct 15.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Marburg, Germany.

Vascular pathologies, such as thrombosis or atherosclerosis, are leading causes of death worldwide and are strongly associated with the dysfunction of vascular endothelial cells. In this context, the extracellular endonuclease Ribonuclease 1 (RNase1) acts as an essential protective factor in regulation and maintenance of vascular homeostasis. However, long-term inflammation causes strong repression of RNase1 expression, thereby promoting endothelial cell dysfunction. This inflammation-mediated downregulation of RNase1 in human endothelial cells is facilitated via histone deacetylase (HDAC) 2, although the underlying molecular mechanisms are still unknown. Here, we report that inhibition of c-Jun N-terminal kinase by small chemical compounds in primary human endothelial cells decreased physiological RNase1 mRNA abundance, while p38 kinase inhibition restored repressed RNase1 expression upon proinflammatory stimulation with tumor necrosis factor alpha (TNF-α) and poly I:C. Moreover, blocking of the p38 kinase- and HDAC2-associated kinase casein kinase 2 (CK2) by inhibitor as well as small interfering RNA (siRNA)-knockdown restored RNase1 expression upon inflammation of human endothelial cells. Further downstream, siRNA-knockdown of chromodomain helicase DNA binding protein (CHD) 3 and 4 of the nucleosome remodeling and deacetylase (NuRD) complex restored RNase1 repression in TNF-α treated endothelial cells implicating its role in the HDAC2-containing repressor complex involved in RNase1 repression. Finally, chromatin immunoprecipitation in primary human endothelial cells confirmed recruitment of the CHD4-containing NuRD complex and subsequent promoter remodeling via histone deacetylation at the promoter in a p38-dependent manner upon human endothelial cell inflammation. Altogether, our results suggest that endothelial RNase1 repression in chronic vascular inflammation is regulated by a p38 kinase-, CK2-, and NuRD complex-dependent pathway resulting in complex recruitment to the promoter and subsequent promoter remodeling.
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http://dx.doi.org/10.3389/fcell.2020.563604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593526PMC
October 2020

Influenza virus-mediated suppression of bronchial Chitinase-3-like 1 secretion promotes secondary pneumococcal infection.

FASEB J 2020 Dec 23;34(12):16432-16448. Epub 2020 Oct 23.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Marburg, Philipps University Marburg, Hesse, Germany.

Infections of the lung are among the leading causes of death worldwide. Despite the preactivation of innate defense programs during viral infection, secondary bacterial infection substantially elevates morbidity and mortality rates. Particularly problematic are co-infections with influenza A virus (IAV) and the major bacterial pathogen Streptococcus pneumoniae. However, the molecular processes underlying the severe course of such co-infections are not fully understood. Previously, the absence of secreted glycoprotein Chitinase-3-like 1 (CHI3L1) was shown to increase pneumococcal replication in mice. We therefore hypothesized that an IAV preinfection decreases CHI3L1 levels to promote pneumococcal infection. Indeed, in an air-liquid interface model of primary human bronchial epithelial cells (hBECs), IAV preinfection interfered with apical but not basolateral CHI3L1 release. Confocal time-lapse microscopy revealed that the gradual loss of apical CHI3L1 localization during co-infection with influenza and S. pneumoniae coincided with the disappearance of goblet as well as ciliated cells and increased S. pneumoniae replication. Importantly, extracellular restoration of CHI3L1 levels using recombinant protein significantly reduced bacterial load in influenza preinfected bronchial models. Thus, recombinant CHI3L1 may provide a novel therapeutic means to lower morbidity and mortality associated with post-influenza pneumococcal infections.
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http://dx.doi.org/10.1096/fj.201902988RRDOI Listing
December 2020

Endothelial Ribonuclease 1 in Cardiovascular and Systemic Inflammation.

Front Cell Dev Biol 2020 4;8:576491. Epub 2020 Sep 4.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Marburg, Germany.

The vascular endothelial cell layer forms the inner lining of all blood vessels to maintain proper functioning of the vascular system. However, dysfunction of the endothelium depicts a major issue in context of vascular pathologies, such as atherosclerosis or thrombosis that cause several million deaths per year worldwide. In recent years, the endothelial extracellular endonuclease Ribonuclease 1 (RNase1) was described as a key player in regulation of vascular homeostasis by protecting endothelial cells from detrimental effects of the damage-associated molecular pattern extracellular RNA upon acute inflammation. Despite this protective function, massive dysregulation of RNase1 was observed during prolonged endothelial cell inflammation resulting in progression of several vascular diseases. For the first time, this review article outlines the current knowledge on endothelial RNase1 and its role in function and dysfunction of the endothelium, thereby focusing on the intensive research from recent years: Uncovering the underlying mechanisms of RNase1 function and regulation in response to acute as well as long-term inflammation, the role of RNase1 in context of vascular, inflammatory and infectious diseases and the potential to develop novel therapeutic options to treat these pathologies against the background of RNase1 function in endothelial cells.
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http://dx.doi.org/10.3389/fcell.2020.576491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500176PMC
September 2020

Detection and segmentation of morphologically complex eukaryotic cells in fluorescence microscopy images via feature pyramid fusion.

PLoS Comput Biol 2020 09 8;16(9):e1008179. Epub 2020 Sep 8.

Department of Mathematics and Computer Science, Philipps-Universität Marburg, Marburg, Germany.

Detection and segmentation of macrophage cells in fluorescence microscopy images is a challenging problem, mainly due to crowded cells, variation in shapes, and morphological complexity. We present a new deep learning approach for cell detection and segmentation that incorporates previously learned nucleus features. A novel fusion of feature pyramids for nucleus detection and segmentation with feature pyramids for cell detection and segmentation is used to improve performance on a microscopic image dataset created by us and provided for public use, containing both nucleus and cell signals. Our experimental results indicate that cell detection and segmentation performance significantly benefit from the fusion of previously learned nucleus features. The proposed feature pyramid fusion architecture clearly outperforms a state-of-the-art Mask R-CNN approach for cell detection and segmentation with relative mean average precision improvements of up to 23.88% and 23.17%, respectively.
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http://dx.doi.org/10.1371/journal.pcbi.1008179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523959PMC
September 2020

Defective BACH1/HO-1 regulatory circuits in cystic fibrosis bronchial epithelial cells.

J Cyst Fibros 2021 Jan 11;20(1):140-148. Epub 2020 Jun 11.

Department of Internal Medicine, Justus-Liebig University, Giessen, Germany; University of Giessen and Marburg Lung Center (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Germany; Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany.

Background: The stress-regulated enzyme hemeoxygenase-1 (HO-1) contributes to the cell response towards inflammation and oxidative stress. We previously reported on curtailed HO-1 expression in cystic fibrosis (CF) bronchial epithelial (CFBE41o-) cells and CF-mice, but the molecular mechanisms for this are not known. Here, we compared healthy and CF bronchial epithelial cells for regulatory circuits controlling HO-1 protein levels.

Methods: In this study, we employed immunohistochemistry on CF and healthy lung sections to examine the BACH1 protein expression. Alteration of BACH1 protein levels in 16HBE14o- and CFBE41o- cells was achieved by using either siRNA-mediated knockdown of BACH1 or by increasing miRNA-155 levels. HO-1 luciferase reporter assay was chosen to examine the downstream affects after BACH1 modulation.

Results: Human CF lungs and cells showed increased levels of the HO-1 transcriptional repressor, BACH1, and increased miR-155 expression. Knockdown studies using BACH1 siRNA and overexpression of miR-155 did not significantly rescue HO-1 expression in CFBE41o- cells. Elevated BACH1 expression detected in CF cells was refractory to the inhibitory function of miR-155 and was instead due to increased protein stability.

Conclusion: We observed defects in the inhibitory activities of miR-155 and BACH1 on HO-1 expression in CF cells. Thus various defective regulatory loops account for dysregulated BACH1 expression in CF, which in turn may contribute to low HO-1 levels.
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http://dx.doi.org/10.1016/j.jcf.2020.05.006DOI Listing
January 2021

Update in Chronic Obstructive Pulmonary Disease 2019.

Am J Respir Crit Care Med 2020 08;202(3):348-355

Department of Medicine, Pulmonary and Critical Care Medicine, Member of the German Center for Lung Research (DZL).

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http://dx.doi.org/10.1164/rccm.202002-0370UPDOI Listing
August 2020

High eosinophil blood counts are associated with a shorter length of hospital stay in exacerbated COPD patients - a retrospective analysis.

Respir Res 2020 May 6;21(1):106. Epub 2020 May 6.

Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Centre for Lung Research (DZL), 35043, Marburg, Germany.

Background: In COPD, the course of the disease including morbidity and mortality is strongly associated with severe exacerbations. The current GOLD recommendations emphasize blood eosinophil counts as a marker for responsiveness to inhaled corticosteroids (ICS). Retrospective analyses from randomized clinical trials indicate a favorable response to systemic corticosteroids in exacerbated COPD patients with blood eosinophils > 2%, however data outside clinical trials are scarce.

Patients And Methods: We retrospectively evaluated data from 1007 cases of patients who were admitted to the University Medical Center Marburg between 01/2013 and 12/2018. All patients had been diagnosed with an acute exacerbation of COPD (ICD-10 J44.0/J44.1). Our analysis was based on a subgroup of 417 patients in whom a full blood cell count was obtained at the day of admission. Patients were predominantly male (63.3%), had a median age of 74 years (IQR 65 years - 83 years) and a median FEV1 of 1.03 l (42.6% predicted). We compared the hospital length of stay and other outcome parameters using established thresholds for the eosinophil blood cell count (100 and 300 eosinophils/μl and 2%).

Results: Patients with low eosinophils (< 2%, <100 cells/μl) had a longer median time in hospital (length of hospital stay - LOS) as compared to patients with high eosinophils (< 2%: 9.31 vs. ≥2%:7 days, and < 100/μl: 10 vs. 100-300/μl: 8 vs. > 300/μl: 7 days). The median CRP was higher in patients with low eosinophils as compared to the other groups (< 2%: 22.7 vs. ≥2%: 9 mg/dl and < 100: 25 vs. 100-300: 13.5 vs. > 300: 7.1 mg/dl). Time to re-hospitalization or time to death did not differ between strata of eosinophils. Sensitivity analysis in a subgroup of patients in which pneumonia was excluded by chest x-ray did not significantly alter the results.

Conclusion: The results support the hypothesis that patients with severe COPD exacerbations and elevated blood eosinophil counts respond better to systemic corticosteroid treatment than patients with a non-eosinophilic exacerbation.
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http://dx.doi.org/10.1186/s12931-020-01365-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204070PMC
May 2020

Identification of microRNAs involved in NOD-dependent induction of pro-inflammatory genes in pulmonary endothelial cells.

PLoS One 2020 30;15(4):e0228764. Epub 2020 Apr 30.

Cardiology and Angiology, Philipps-University Marburg, Marburg, Germany.

The nucleotide-binding oligomerization domain-containing proteins (NOD) 1 and 2 are mammalian cytosolic pattern recognition receptors sensing bacterial peptidoglycan fragments in order to initiate cytokine expression and pathogen host defense. Since endothelial cells are relevant cells for pathogen recognition at the blood/tissue interface, we here analyzed the role of NOD1- and NOD2-dependently expressed microRNAs (miRNAs, miR) for cytokine regulation in murine pulmonary endothelial cells. The induction of inflammatory cytokines in response to NOD1 and NOD2 was confirmed by increased expression of tumour necrosis factor (Tnf)-α and interleukin (Il)-6. MiRNA expression profiling revealed NOD1- and NOD2-dependently regulated miRNA candidates, of which miR-147-3p, miR-200a-3p, and miR-298-5p were subsequently validated in pulmonary endothelial cells isolated from Nod1/2-deficient mice. Analysis of the two down-regulated candidates miR-147-3p and miR-298-5p revealed predicted binding sites in the 3' untranslated region (UTR) of the murine Tnf-α and Il-6 mRNA. Consequently, transfection of endothelial cells with miRNA mimics decreased Tnf-α and Il-6 mRNA levels. Finally, a novel direct interaction of miR-298-5p with the 3' UTR of the Il-6 mRNA was uncovered by luciferase reporter assays. We here identified a mechanism of miRNA-down-regulation by NOD stimulation thereby enabling the induction of inflammatory gene expression in endothelial cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228764PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192443PMC
July 2020

Noncoding RNA is an integral component of the TLR4-TRIF pathway.

Proc Natl Acad Sci U S A 2020 04 2;117(16):9042-9053. Epub 2020 Apr 2.

Institute for Lung Research, Philipps-University, 35043 Marburg, Germany;

RNA has been proposed as an important scaffolding factor in the nucleus, aiding protein complex assembly in the dense intracellular milieu. Architectural contributions of RNA to cytosolic signaling pathways, however, remain largely unknown. Here, we devised a multidimensional gradient approach, which systematically locates RNA components within cellular protein networks. Among a subset of noncoding RNAs (ncRNAs) cosedimenting with the ubiquitin-proteasome system, our approach unveiled ncRNA as a critical structural component of the Toll-like receptor 4 (TLR4) immune signal transduction pathway. RNA affinity antisense purification-mass spectrometry (RAP-MS) revealed binding to optineurin (OPTN), a ubiquitin-adapter platforming TBK1 kinase. binding stabilized OPTN, and consequently, loss of blunted OPTN aggregation, TBK1-dependent IRF3 phosphorylation, and type I interferon (IFN) gene transcription downstream of TLR4. expression was elevated in patients with active pulmonary infection and was highly correlated with IFN levels in bronchoalveolar lavage fluid. Our study uncovers as an integral RNA component of the TLR4-TRIF pathway and predicts further RNAs to be required for assembly and progression of cytosolic signaling networks in mammalian cells.
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http://dx.doi.org/10.1073/pnas.1920393117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183186PMC
April 2020

A MicroRNA Network Controls Replication in Human Macrophages via LGALS8 and MX1.

mBio 2020 03 24;11(2). Epub 2020 Mar 24.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps University Marburg, Marburg, Germany

is an important cause of pneumonia. It invades alveolar macrophages and manipulates the immune response by interfering with signaling pathways and gene transcription to support its own replication. MicroRNAs (miRNAs) are critical posttranscriptional regulators of gene expression and are involved in defense against bacterial infections. Several pathogens have been shown to exploit the host miRNA machinery to their advantage. We therefore hypothesize that macrophage miRNAs exert positive or negative control over intracellular replication. We found significant regulation of 85 miRNAs in human macrophages upon infection. Chromatin immunoprecipitation and sequencing revealed concordant changes of histone acetylation at the putative promoters. Interestingly, a trio of miRNAs (miR-125b, miR-221, and miR-579) was found to significantly affect intracellular replication in a cooperative manner. Using proteome-analysis, we pinpointed this effect to a concerted downregulation of galectin-8 (LGALS8), DExD/H-box helicase 58 (DDX58), tumor protein P53 (TP53), and then MX dynamin-like GTPase 1 (MX1) by the three miRNAs. In summary, our results demonstrate a new miRNA-controlled immune network restricting replication in human macrophages. Cases of pneumonia occur worldwide, with potentially fatal outcome. When causing human disease, injects a plethora of virulence factors to reprogram macrophages to circumvent immune defense and create a replication niche. By analyzing -induced changes in miRNA expression and genomewide chromatin modifications in primary human macrophages, we identified a cell-autonomous immune network restricting growth. This network comprises three miRNAs governing expression of the cytosolic RNA receptor DDX58/RIG-I, the tumor suppressor TP53, the antibacterial effector LGALS8, and MX1, which has been described as an antiviral factor. Our findings for the first time link TP53, LGALS8, DDX58, and MX1 in one miRNA-regulated network and integrate them into a functional node in the defense against .
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http://dx.doi.org/10.1128/mBio.03155-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157531PMC
March 2020

Caspase-11 promotes allergic airway inflammation.

Nat Commun 2020 02 26;11(1):1055. Epub 2020 Feb 26.

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI)Trinity College Dublin, Dublin, Ireland.

Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E (PGE) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE production with indomethacin enhances, whereas the prostaglandin E analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.
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http://dx.doi.org/10.1038/s41467-020-14945-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044193PMC
February 2020

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation.

Sci Rep 2020 01 14;10(1):241. Epub 2020 Jan 14.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany.

Lower respiratory infections, such as community-acquired pneumonia (CAP), and chronic obstructive pulmonary disease (COPD) rank among the most frequent causes of death worldwide. Improved diagnostics and profound pathophysiological insights are urgent clinical needs. In our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (PBMCs) to identify central regulators and potential biomarkers. We investigated the mRNA- and miRNA-transcriptome of PBMCs of healthy subjects and patients suffering from CAP or AECOPD by microarray and Taqman Low Density Array. Genes that correlated with PBMC composition were eliminated, and remaining differentially expressed genes were grouped into modules. One selected module (120 genes) was particularly suitable to discriminate AECOPD and CAP and most notably contained a subset of five biologically relevant mRNAs that differentiated between CAP and AECOPD with an AUC of 86.1%. Likewise, we identified several microRNAs, e.g. miR-545-3p and miR-519c-3p, which separated AECOPD and CAP. We furthermore retrieved an integrated network of differentially regulated mRNAs and microRNAs and identified HNF4A, MCC and MUC1 as central network regulators or most important discriminatory markers. In summary, transcriptional analysis retrieved potential biomarkers and central molecular features of CAP and AECOPD.
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http://dx.doi.org/10.1038/s41598-019-57108-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959367PMC
January 2020

IL-17 CD8 T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis.

Nat Commun 2019 12 16;10(1):5722. Epub 2019 Dec 16.

Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany.

IL-17-producing CD8 (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8 T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond.
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http://dx.doi.org/10.1038/s41467-019-13731-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915776PMC
December 2019

NF-κB-mediated inhibition of microRNA-149-5p regulates Chitinase-3-like 1 expression in human airway epithelial cells.

Cell Signal 2020 03 16;67:109498. Epub 2019 Dec 16.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Hans-Meerwein Straße 2, 35043 Marburg, Hesse, Germany. Electronic address:

Lower respiratory tract infections are among the most common causes of death worldwide. Main pathogens leading to these severe infections are viruses and gram-positive bacteria that activate toll-like receptor (TLR)-mediated immune responses via pathogen-associated molecular patterns. One protective factor induced during infection is Chitinase-3-like 1 (CHI3L1), which exerts various functions, e.g. in host cell proliferation and bacterial counteraction, and has been proposed as a biomarker in several acute and chronic inflammatory conditions. MicroRNAs (miR) have become important regulators of inflammation and infection and are considered therapeutic targets in recent years. However, it is not known whether microRNAs play a role in the regulation of CHI3L1 expression in TLR-mediated respiratory epithelial cell inflammation. In this study, we analysed the pre- and post-transcriptional regulation of CHI3L1 by TLRs in bronchial epithelial cells. Therefore, we stimulated BEAS-2B cells with the bacterial TLR2-ligand lipoteichoic acid or the viral dsRNA analogue poly(I:C). We observed an increase in the expression of CHI3L1, which was dependent on TNF-α-mediated NF-κB activation in TLR2- and TLR3-activated cells. Moreover, TLR2 and - 3 stimulation caused downregulation of the microRNA miR-149-5p, an effect that could be suppressed by inhibiting NF-κB translocation into the nucleus. Luciferase reporter assays identified a direct interaction of miR-149-5p with the CHI3L1 3´untranslated region. This interaction was confirmed by inhibition and overexpression of miR-149-5p in BEAS-2B cells, which altered the expression levels of CHI3L1 mRNA. In summary, miR-149-5p directly regulates CHI3L1 in context of TLR-mediated airway epithelial cell inflammation and may be a potential therapeutic target in inflammation and other diseases.
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http://dx.doi.org/10.1016/j.cellsig.2019.109498DOI Listing
March 2020

Antibacterial activity of a defensin in an infection model of .

Virulence 2019 12;10(1):902-909

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany.

() is the most common bacterial cause of community-acquired pneumonia. Increasing rates of antibiotic-resistant strains impair therapy and necessitate alternative treatment options. In this study, we analysed insect-derived antimicrobial peptides (AMPs) for antibacterial effects on in a human infection model.AMP effects on bacterial growth were examined by colony forming unit (CFU)-assays, and growth curve measurements. Furthermore, cytotoxicity to primary human macrophages was detected by measuring lactate-dehydrogenase release to the supernatant. One AMP (Defensin 1) was tested in a model of primary human monocyte-derived macrophages infected with strain D39 and a multi-resistant clinical isolate. Inflammatory reactions were characterised by qPCR and multiplex-ELISA.In total, the antibacterial effects of 23 AMPs were characterized. Only Defensin 1 showed significant antibacterial effects against strain D39 and a multi-resistant clinical isolate. During infection of primary human macrophages with D39, Defensin 1 displayed strong antibacterial effects, and consequently reduced bacteria-induced cytokine expression and release.In summary, Defensin 1 showed profound antibacterial effectivity against D39 and a multi-resistant clinical isolate without unwanted cytotoxic or inflammatory side effects on human blood-derived macrophages.
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http://dx.doi.org/10.1080/21505594.2019.1685150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844301PMC
December 2019

Surface Proteome of Plasma Extracellular Vesicles as Biomarkers for Pneumonia and Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

J Infect Dis 2020 01;221(2):325-335

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Member of the German Center for Lung Research, Marburg, Germany.

Background: Community-acquired pneumonia (CAP) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) represent a major burden of disease and death and their differential diagnosis is critical. A potential source of relevant accessible biomarkers are blood-borne small extracellular vesicles (sEVs).

Methods: We performed an extracellular vesicle array to find proteins on plasma sEVs that are differentially expressed and possibly allow the differential diagnosis between CAP and AECOPD. Plasma samples were analyzed from 21 healthy controls, 24 patients with CAP, and 10 with AECOPD . The array contained 40 antibodies to capture sEVs, which were then visualized with a cocktail of biotin-conjugated CD9, CD63, and CD81 antibodies.

Results: We detected significant differences in the protein decoration of sEVs between healthy controls and patients with CAP or AECOPD. We found CD45 and CD28 to be the best discrimination markers between CAP and AECOPD in receiver operating characteristic analyses, with an area under the curve >0.92. Additional ensemble feature selection revealed the possibility to distinguish between CAP and AECOPD even if the patient with CAP had COPD, with a panel of CD45, CD28, CTLA4 (cytotoxic T-lymphocyte-associated protein 4), tumor necrosis factor-R-II, and CD16.

Conclusion: The discrimination of sEV-associated proteins is a minimally invasive method with potential to discriminate between CAP and AECOPD.
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http://dx.doi.org/10.1093/infdis/jiz460DOI Listing
January 2020

Peptidoglycan Recognition Protein 4 Limits Bacterial Clearance and Inflammation in Lungs by Control of the Gut Microbiota.

Front Immunol 2019 20;10:2106. Epub 2019 Sep 20.

Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

is the most frequent cause of community-acquired pneumonia. Endogenous host defense molecules such as peptidoglycan recognition protein 4 (PGLYRP4) might influence the course of this disease. To the best of our knowledge, there are no reports on the relevance of PGLYRP4 in pneumonia. Therefore, wild type (WT) and PGLYRP4-deficient (PGLYRP4KO) mice were analyzed in an and experimental setting to examine the influence of PGLYRP4 on the course of pneumococcal pneumonia. Furthermore, caecal 16S rRNA microbiome analysis was performed, and microbiota were transferred to germfree WT mice to assess the influence of microbiotal communities on the bacterial burden. Mice lacking PGLYRP4 displayed an enhanced bacterial clearance in the lungs, and fewer mice developed bacteremia. In addition, an increased recruitment of immune cells to the site of infection, and an enhanced bacterial killing by stronger activation of phagocytes could be shown. This may depend partly on the detected higher expression of complement factors, interferon-associated genes, and the higher pro-inflammatory cytokine response in isolated primary PGLYRP4KO vs. WT cells. This phenotype is underlined by changes in the complexity and composition of the caecal microbiota of PGLYRP4KO compared to WT mice. Strikingly, we provided evidence, by cohousing and stable transfer of the respective WT or PGLYRP4KO mice microbiota into germfree WT mice, that the changes of the microbiota are responsible for the improved clearance of lung infection. In conclusion, the deficiency of PGLYRP4, a known antibacterial protein, leads to changes in the gut microbiota. Thus, alterations in the microbiota can change the susceptibility to lung infection independently of the host genotype.
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http://dx.doi.org/10.3389/fimmu.2019.02106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763742PMC
October 2020

TMPRSS2 Is the Major Activating Protease of Influenza A Virus in Primary Human Airway Cells and Influenza B Virus in Human Type II Pneumocytes.

J Virol 2019 11 15;93(21). Epub 2019 Oct 15.

Institute of Virology, Philipps University, Marburg, Germany

Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is essential for virus infectivity and spread. We previously demonstrated that the transmembrane protease TMPRSS2 cleaves influenza A virus (IAV) and influenza B virus (IBV) HA possessing a monobasic cleavage site. Subsequent studies revealed that TMPRSS2 is crucial for the activation and pathogenesis of H1N1pdm and H7N9 IAV in mice. In contrast, activation of H3N2 IAV and IBV was found to be independent of TMPRSS2 expression and supported by an as-yet-undetermined protease(s). Here, we investigated the role of TMPRSS2 in proteolytic activation of IAV and IBV in three human airway cell culture systems: primary human bronchial epithelial cells (HBEC), primary type II alveolar epithelial cells (AECII), and Calu-3 cells. Knockdown of TMPRSS2 expression was performed using a previously described antisense peptide-conjugated phosphorodiamidate morpholino oligomer, T-ex5, that interferes with splicing of pre-mRNA, resulting in the expression of enzymatically inactive TMPRSS2. T-ex5 treatment produced efficient knockdown of active TMPRSS2 in all three airway cell culture models and prevented proteolytic activation and multiplication of H7N9 IAV in Calu-3 cells and H1N1pdm, H7N9, and H3N2 IAV in HBEC and AECII. T-ex5 treatment also inhibited the activation and spread of IBV in AECII but did not affect IBV activation in HBEC and Calu-3 cells. This study identifies TMPRSS2 as the major HA-activating protease of IAV in human airway cells and IBV in type II pneumocytes and as a potential target for the development of novel drugs to treat influenza infections. Influenza A viruses (IAV) and influenza B viruses (IBV) cause significant morbidity and mortality during seasonal outbreaks. Cleavage of the viral surface glycoprotein hemagglutinin (HA) by host proteases is a prerequisite for membrane fusion and essential for virus infectivity. Inhibition of relevant proteases provides a promising therapeutic approach that may avoid the development of drug resistance. HA of most influenza viruses is cleaved at a monobasic cleavage site, and a number of proteases have been shown to cleave HA This study demonstrates that the transmembrane protease TMPRSS2 is the major HA-activating protease of IAV in primary human bronchial cells and of both IAV and IBV in primary human type II pneumocytes. It further reveals that human and murine airway cells can differ in their HA-cleaving protease repertoires. Our data will help drive the development of potent and selective protease inhibitors as novel drugs for influenza treatment.
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http://dx.doi.org/10.1128/JVI.00649-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803253PMC
November 2019

Personalized medicine for patients with COPD: where are we?

Int J Chron Obstruct Pulmon Dis 2019 9;14:1465-1484. Epub 2019 Jul 9.

Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany.

Chronic airflow limitation is the common denominator of patients with chronic obstructive pulmonary disease (COPD). However, it is not possible to predict morbidity and mortality of individual patients based on the degree of lung function impairment, nor does the degree of airflow limitation allow guidance regarding therapies. Over the last decades, understanding of the factors contributing to the heterogeneity of disease trajectories, clinical presentation, and response to existing therapies has greatly advanced. Indeed, diagnostic assessment and treatment algorithms for COPD have become more personalized. In addition to the pulmonary abnormalities and inhaler therapies, extra-pulmonary features and comorbidities have been studied and are considered essential components of comprehensive disease management, including lifestyle interventions. Despite these advances, predicting and/or modifying the course of the disease remains currently impossible, and selection of patients with a beneficial response to specific interventions is unsatisfactory. Consequently, non-response to pharmacologic and non-pharmacologic treatments is common, and many patients have refractory symptoms. Thus, there is an ongoing urgency for a more targeted and holistic management of the disease, incorporating the basic principles of P4 medicine (predictive, preventive, personalized, and participatory). This review describes the current status and unmet needs regarding personalized medicine for patients with COPD. Also, it proposes a systems medicine approach, integrating genetic, environmental, (micro)biological, and clinical factors in experimental and computational models in order to decipher the multilevel complexity of COPD. Ultimately, the acquired insights will enable the development of clinical decision support systems and advance personalized medicine for patients with COPD.
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http://dx.doi.org/10.2147/COPD.S175706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636434PMC
February 2020

Inflammation-mediated deacetylation of the ribonuclease 1 promoter histone deacetylase 2 in endothelial cells.

FASEB J 2019 08 30;33(8):9017-9029. Epub 2019 Apr 30.

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, German Center for Lung Research (DZL), Marburg, Germany.

Ribonuclease 1 (RNase1) is a circulating extracellular endonuclease that regulates the vascular homeostasis of extracellular RNA and acts as a vessel- and tissue-protective enzyme. Upon long-term inflammation, high amounts of proinflammatory cytokines affect endothelial cell (EC) function by down-regulation of RNase1. Here, we investigated the transcriptional regulation of RNase1 upon inflammation in HUVECs. TNF-α or IL-1β stimulation reduced the expression of RNase1 relative to the acetylation state of histone 3 at lysine 27 and histone 4 of the promoter. Inhibition of histone deacetylase (HDAC) 1, 2, and 3 by the specific class I HDAC inhibitor MS275 abolished the TNF-α- or IL-1β-mediated effect on the mRNA and chromatin levels of RNase1. Moreover, chromatin immunoprecipitation kinetics revealed that HDAC2 accumulates at the promoter upon TNF-α stimulation, indicating an essential role for HDAC2 in regulating RNase1 expression. Thus, proinflammatory stimulation induced recruitment of HDAC2 to attenuate histone acetylation at the promoter site. Consequently, treatment with HDAC inhibitors may provide a new therapeutic strategy to stabilize vascular homeostasis in the context of inflammation by preventing RNase1 down-regulation in ECs.-Bedenbender, K., Scheller, N., Fischer, S., Leiting, S., Preissner, K. T., Schmeck, B. T., Vollmeister, E. Inflammation-mediated deacetylation of the ribonuclease 1 promoter histone deacetylase 2 in endothelial cells.
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http://dx.doi.org/10.1096/fj.201900451RDOI Listing
August 2019

Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cells.

J Clin Invest 2019 04 2;129(5):1972-1983. Epub 2019 Apr 2.

Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany.

The impact of food antigens on intestinal homeostasis and immune function is poorly understood. Here, we explored the impact of dietary antigens on the phenotype and fate of intestinal T cells. Physiological uptake of dietary proteins generated a highly activated CD44+Helios+CD4+ T cell population predominantly in Peyer patches. These cells are distinct from regulatory T cells and develop independently of the microbiota. Alimentation with a protein-free, elemental diet led to an atrophic small intestine with low numbers of activated T cells, including Tfh cells and decreased amounts of intestinal IgA and IL-10. Food-activated CD44+Helios+CD4+ T cells in the Peyer patches are controlled by the immune checkpoint molecule PD-1. Blocking the PD-1 pathway rescued these T cells from apoptosis and triggered proinflammatory cytokine production, which in IL-10-deficient mice was associated with intestinal inflammation. In support of these findings, our study of patients with Crohn's disease revealed significantly reduced frequencies of apoptotic CD4+ T cells in Peyer patches as compared with healthy controls. These results suggest that apoptosis of diet-activated T cells is a hallmark of the healthy intestine.
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http://dx.doi.org/10.1172/JCI98929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486345PMC
April 2019

Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signalling.

Nat Microbiol 2019 04 25;4(4):701-713. Epub 2019 Feb 25.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

The innate immune system is crucial for eventual control of infections, but may also contribute to pathology. Listeria monocytogenes is an intracellular Gram-positive bacteria and a major cause of food-borne disease. However, important knowledge on the interactions between L. monocytogenes and the immune system is still missing. Here, we report that Listeria DNA is sorted into extracellular vesicles (EVs) in infected cells and delivered to bystander cells to stimulate the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway. This was also observed during infections with Francisella tularensis and Legionella pneumophila. We identify the multivesicular body protein MVB12b as a target for TANK-binding kinase 1 phosphorylation, which is essential for the sorting of DNA into EVs and stimulation of bystander cells. EVs from Listeria-infected cells inhibited T-cell proliferation, and primed T cells for apoptosis. Collectively, we describe a pathway for EV-mediated delivery of foreign DNA to bystander cells, and suggest that intracellular bacteria exploit this pathway to impair antibacterial defence.
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http://dx.doi.org/10.1038/s41564-019-0367-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433288PMC
April 2019

ncRNAs in Inflammatory and Infectious Diseases.

Methods Mol Biol 2019 ;1912:3-32

Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany.

Inflammatory and infectious diseases are among the main causes of morbidity and mortality worldwide. Inflammation is central to maintenance of organismal homeostasis upon infection, tissue damage, and malignancy. It occurs transiently in response to diverse stimuli (e.g., physical, radioactive, infective, pro-allergenic, or toxic), and in some cases may manifest itself in chronic diseases. To limit the potentially deleterious effects of acute or chronic inflammatory responses, complex transcriptional and posttranscriptional regulatory networks have evolved, often involving nonprotein-coding RNAs (ncRNA). MicroRNAs (miRNAs) are a class of posttranscriptional regulators that control mRNA translation and stability. Long ncRNAs (lncRNAs) are a very diverse group of transcripts >200 nt, functioning among others as scaffolds or decoys both in the nucleus and the cytoplasm. By now, it is well established that miRNAs and lncRNAs are implicated in all major cellular processes including control of cell death, proliferation, or metabolism. Extensive research over the last years furthermore revealed a fundamental role of ncRNAs in pathogen recognition and inflammatory responses. This chapter reviews and summarizes the current knowledge on regulatory ncRNA networks in infection and inflammation.
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http://dx.doi.org/10.1007/978-1-4939-8982-9_1DOI Listing
June 2019

Proviral MicroRNAs Detected in Extracellular Vesicles From Bronchoalveolar Lavage Fluid of Patients With Influenza Virus-Induced Acute Respiratory Distress Syndrome.

J Infect Dis 2019 01;219(4):540-543

Institute for Lung Research, Universities of Giessen and Marburg Lung Center.

Influenza A virus (IAV) causes severe respiratory infections and alveolar epithelial damage resulting in acute respiratory distress syndrome (ARDS). Extracellular vesicles (EVs) have been shown to mediate cellular crosstalk in inflammation by transfer of microRNAs (miRNAs). In this study, we found significant changes in the miRNA composition of EVs in the bronchoalveolar lavage fluid from patients with IAV-induced ARDS. Among the 9 significantly deregulated microRNAs, miR-17-5p was upregulated in patients' BALF and in EVs of IAV-infected lung epithelial cells (A549). In these cells, transfer of miR-17-5p strongly downregulated expression of the antiviral factor Mx1 and significantly enhanced IAV replication.
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http://dx.doi.org/10.1093/infdis/jiy554DOI Listing
January 2019