13 results on '"Fliesser, Mirjam"'
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2. Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune responses initiated by human dendritic cells
- Author
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Fliesser, Mirjam, Morton, Charles Oliver, Bonin, Michael, Ebel, Frank, Hünniger, Kerstin, Kurzai, Oliver, Einsele, Hermann, and Löffler, Jürgen
- Published
- 2015
- Full Text
- View/download PDF
3. First Insights in NK—DC Cross-Talk and the Importance of Soluble Factors During Infection With Aspergillus fumigatus
- Author
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Weiss, Esther, primary, Ziegler, Sabrina, additional, Fliesser, Mirjam, additional, Schmitt, Anna-Lena, additional, Hünniger, Kerstin, additional, Kurzai, Oliver, additional, Morton, Charles-Oliver, additional, Einsele, Hermann, additional, and Loeffler, Juergen, additional
- Published
- 2018
- Full Text
- View/download PDF
4. Hypoxie und Hypoxie-induzierbarer Faktor 1α modulieren die Immunantwort humaner dendritischer Zellen gegenüber Aspergillus fumigatus
- Author
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Fließer, Mirjam
- Subjects
ddc:616 ,Hypoxie ,Dendritische Zelle ,Aspergillus fumigatus ,Immunologie ,ddc:579 - Abstract
The mold Aspergillus fumigatus causes life-threatening infections in immunocompromised patients. Over the past decade new findings in research have improved our understanding of A. fumigatus-host interactions. One of them was the detection of localized areas of tissue hypoxia in the lungs of mice infected with A. fumigatus. The transcription factor hypoxia-inducible factor 1α (HIF 1α) is known as the central regulator of cellular responses to hypoxia. Under normoxia, this constitutively expressed protein is degraded by oxygen-dependent mechanisms in most mammalian cell types. Interaction with pathogens can induce HIF 1α stabilization under normoxic conditions in innate immune cells. Bacterial infection models revealed that hypoxic microenvironments and signaling via HIF 1α modulate functions of host immune cells. Moreover, it was recently described that in murine phagocytes, HIF 1α expression is essential to overcome an A. fumigatus infection. However, the influence of hypoxia and the role of HIF 1α signaling for anti-A. fumigatus immunity is still poorly understood, especially regarding dendritic cells (DCs), which are important regulators of anti-fungal immunity. In this study, the functional relevance of hypoxia and HIF 1α signaling in the response of human DCs against A. fumigatus has been investigated. Hypoxia attenuated the pro-inflammatory response of DCs against A. fumigatus during the initial infection as shown by genome-wide microarray expression analyses and cytokine quantification. The up-regulation of maturation-associated molecules on DCs stimulated with A. fumigatus under hypoxia was reduced; however, these DCs possessed an enhanced capacity to stimulate T cells. This study thereby revealed divergent influence of hypoxia on anti-A. fumigatus DC functions that included both, inhibiting and enhancing effects. HIF-1α was stabilized in DCs following stimulation with A. fumigatus under normoxic and hypoxic conditions. This stabilization was partially dependent on Dectin-1, the major receptor for A. fumigatus on human DCs. Using siRNA-based HIF 1α silencing combined with gene expression microarrays, a modulatory effect of HIF-1α on the anti-fungal immune response of human DCs was identified. Specifically, the transcriptomes of HIF-1α silenced DCs indicated that HIF-1α enhanced DC metabolism and cytokine release in response to A. fumigatus under normoxic and hypoxic conditions. This was confirmed by further down-stream analyses that included quantification of glycolytic activity and cytokine profiling of DCs. By that, this study demonstrated functional relevance of HIF 1α expression in DCs responding to A. fumigatus. The data give novel insight into the cellular functions of HIF 1α in human DCs that include regulation of the anti-fungal immune response under normoxia and hypoxia. The comprehensive transcriptome datasets in combination with the down-stream protein analyses from this study will promote further investigations to further characterize the complex interplay between hypoxia, activation of Dectin-1 and HIF-1α signaling in host responses against A. fumigatus., Der Schimmelpilz Aspergillus fumigatus verursacht lebensbedrohliche Infektionen in immunsupprimierten Patienten. Im letzten Jahrzehnt haben neue Forschungsergebnisse unser Verständnis der Interaktion von A. fumigatus mit seinem Wirt verbessert. Dazu zählt die Beschreibung von lokalisierten Arealen der Hypoxie im Lungengewebe von Mäusen die mit A. fumigatus infiziert wurden. Der Transkriptionsfaktor Hypoxie-induzierbarer Faktor 1α (HIF 1α) ist schon lange als der zentrale Regulator der zellulären Antwort gegenüber Hypoxie bekannt. Unter Normoxie wird dieses konstitutiv exprimierte Protein in den meisten Körperzellen durch sauerstoffabhängige Prozesse abgebaut. In angeborenen Immunzellen kann die Interaktion mit Pathogenen zu einer Stabilisierung von HIF 1α unter normoxischen Bedingungen führen. Bakterielle Infektionsmodelle haben gezeigt, dass hypoxische Mikromilieus und der HIF 1α Signalweg die Funktion von Immunzellen des Wirtes beeinflussen können. Zudem konnte kürzlich nachgewiesen werden, dass die Expression von HIF 1α in murinen Phagozyten während einer Infektion mit A. fumigtus essentiell für eine effektive Bekämpfung des Pilzes ist. Der Einfluss der Hypoxie und die Rolle von HIF 1α für die gegen A. fumigatus gerichtete Immunantwort sind jedoch immer noch unzureichend charakterisiert. Das trifft besonders auf die für die Regulation der anti-fungalen Immunantwort wichtigen dendritischen Zellen (DCs) zu. In dieser Studie wurde die funktionale Bedeutung der Hypoxie und des HIF 1α Signalweges für die Antwort humaner DCs gegenüber A. fumigatus untersucht. Hypoxie hatte einen abschwächenden Effekt auf die initiale pro-inflammatorische Antwort von DCs gegen A. fumigatus. Dies konnte durch genomweite Microarray Expressionsanalysen sowie Zytokinbestimmungen gezeigt werden. Die Hochregulation von Markern, die mit einer Maturierung von mit A. fumigatus-stimulierten DCs assoziiert sind, war unter Hypoxie reduziert. Jedoch zeigten diese DCs eine erhöhte Fähigkeit zur Stimulation von T Zellen. Damit wurden in dieser Studie divergente Effekte der Hypoxie auf die gegen A. fumigatus gerichtete Immunantwort humaner DCs aufgedeckt. Dies beinhaltete sowohl einen inhibierenden als auch einen verstärkenden Einfluss in Abhängigkeit der untersuchten DC Funktion. HIF 1α wurde in DCs nach Stimulation mit A. fumigatus unter normoxischen als auch hypoxischen Bedingungen stabilisiert. Diese Stabilisierung war teilweise abhängig von Dectin-1, dem wichtigsten Rezeptor für A. fumigatus auf humanen DCs. Durch eine Kombination aus RNAi-vermittelter Herunterregulation von HIF 1α und Genexpressions-Microarrays wurde ein modulierender Effekt von HIF 1α auf die anti-fungale Immunantwort humaner DCs identifiziert. Die Transkriptomanalyse von HIF 1α herunterregulierten DCs deutete darauf hin, dass HIF 1α den Metabolismus und die Zytokinfreisetzung in DCs während der Antwort auf A. fumigatus unter normoxischen als auch hypoxischen Bedingungen verstärkt. Dieser Befund wurde durch weiterführende Analysen bestätigt, die eine Quantifizierung der glykolytischen Aktivität sowie die Erstellung eines Zytokinprofils der DCs beinhalteten. Damit konnte in dieser Studie eine funktionale Relevanz der Expression von HIF 1α in DCs für die gegen A. fumigatus gerichtete Immunantwort aufgedeckt werden. Diese Daten geben einen neuen Einblick in die zellulären Funktionen von HIF 1α in humanen DCs, die eine Regulierung der anti-fungalen Immunantwort beinhalten. Die umfassenden Transkriptom-Datensätze dieser Studie, die durch Proteinanalysen funktional ergänzt wurden, bilden die Grundlage für weiterführende Untersuchungen. Damit wird es möglich sein, das komplexe Zusammenspiel aus Hypoxie, Aktivierung von Dectin-1 und Signalübertragung über HIF 1α in der Immunantwort gegen A. fumigatus über die Ergebnisse dieser Studie hinaus noch besser zu charakterisieren.
- Published
- 2015
5. Aspergillus fumigatus induces microRNA-132 in human monocytes and dendritic cells
- Author
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Das Gupta, Mithun, Fliesser, Mirjam, Springer, Jan, Breitschopf, Tanja, Schlossnagel, Hannes, Schmitt, Anna-Lena, Kurzai, Oliver, Hünniger, Kerstin, Einsele, Hermann, and Löffler, Jürgen
- Published
- 2014
- Full Text
- View/download PDF
6. Gene expression profiles of human dendritic cells interacting with Aspergillus fumigatus in a bilayer model of the alveolar epithelium/endothelium interface
- Author
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Morton, Charles Oliver, Fliesser, Mirjam, Dittrich, Marcus, Mueller, Tobias, Bauer, Ruth, Kneitz, Susanne, Hope, William, Rogers, Thomas Richard, Einsele, Hermann, and Loeffler, Juergen
- Subjects
Immune Cells ,Immunology ,Lipid Bilayers ,Protein Array Analysis ,Antigen-Presenting Cells ,Gene Expression ,lcsh:Medicine ,Mycology ,Pathogenesis ,Respiratory Mucosa ,Pathology and Laboratory Medicine ,Microbiology ,Cell Line ,Animal Cells ,Molecular Cell Biology ,Genetics ,Medicine and Health Sciences ,Aspergillosis ,Humans ,ddc:610 ,lcsh:Science ,Immune Response ,Reverse Transcriptase Polymerase Chain Reaction ,Aspergillus fumigatus ,lcsh:R ,Organisms ,Fungi ,Fungal Diseases ,Biology and Life Sciences ,Cell Biology ,Dendritic Cells ,respiratory system ,Pulmonary Alveoli ,Infectious Diseases ,Gene Ontology ,Gene Expression Regulation ,Medical Microbiology ,Host-Pathogen Interactions ,lcsh:Q ,Endothelium, Vascular ,Pulmonary Aspergillosis ,Cellular Types ,Transcriptome ,Research Article - Abstract
The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.
- Published
- 2014
7. Human primary myeloid dendritic cells interact with the opportunistic fungal pathogenAspergillus fumigatusvia the C-type lectin receptor Dectin-1
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Hefter, Maike, primary, Lother, Jasmin, additional, Weiß, Esther, additional, Schmitt, Anna Lena, additional, Fliesser, Mirjam, additional, Einsele, Hermann, additional, and Loeffler, Juergen, additional
- Published
- 2016
- Full Text
- View/download PDF
8. Hypoxia attenuates anti-Aspergillus fumigatusimmune responses initiated by human dendritic cells
- Author
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Fliesser, Mirjam, primary, Wallstein, Marion, additional, Kurzai, Oliver, additional, Einsele, Hermann, additional, and Löffler, Jürgen, additional
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- 2016
- Full Text
- View/download PDF
9. Genome-Wide Expression Profiling Reveals S100B as Biomarker for Invasive Aspergillosis
- Author
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Dix, Andreas, primary, Czakai, Kristin, additional, Springer, Jan, additional, Fliesser, Mirjam, additional, Bonin, Michael, additional, Guthke, Reinhard, additional, Schmitt, Anna L., additional, Einsele, Hermann, additional, Linde, Jörg, additional, and Löffler, Jürgen, additional
- Published
- 2016
- Full Text
- View/download PDF
10. Human primary myeloid dendritic cells interact with the opportunistic fungal pathogen Aspergillus fumigatus via the C-type lectin receptor Dectin-1.
- Author
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Hefter, Maike, Lother, Jasmin, Weiß, Esther, Schmitt, Anna Lena, Fliesser, Mirjam, Einsele, Hermann, and Loeffler, Juergen
- Abstract
Aspergillus fumigatus is an opportunistic fungal pathogen causing detrimental infections in immunocompromised individuals. Dendritic cells (DCs) are potent antigen-presenting cells and recognize the A. fumigatus cell wall component β-1,3 glucan via Dectin-1, followed by DCmaturation and cytokine release. Here, we demonstrate that human primary myeloid DCs (mDCs) interact with different morphotypes of A. fumigatus. Dectin-1 is expressed on mDCs and is down-regulated after contact with A. fumigatus, indicating that mDCs recognize A. fumigatus via this receptor. Blocking of Dectin-1, followed by stimulation with depleted zymosan diminished the up-regulation of the T-cell co-stimulatory molecules CD40, CD80, HLA-DR and CCR7 on mDCs and led to decreased release of the cytokines TNF-α, IL-8, IL-1β and IL-10. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
11. Hypoxia attenuates anti- Aspergillus fumigatus immune responses initiated by human dendritic cells.
- Author
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Fliesser, Mirjam, Wallstein, Marion, Kurzai, Oliver, Einsele, Hermann, and Löffler, Jürgen
- Subjects
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PULMONARY aspergillosis , *HYPOXEMIA , *ASPERGILLUS fumigatus , *IMMUNOREGULATION , *DENDRITIC cells , *IMMUNOCOMPROMISED patients , *THERAPEUTICS , *PHYSIOLOGY - Abstract
Aspergillus fumigatus is an opportunistic mould that causes invasive pulmonary aspergillosis ( IPA), a life-threatening infection in immunocompromised patients. During the course of IPA, localised areas of tissue hypoxia occur. Bacterial infection models revealed that hypoxic microenvironments modulate the function of host immune cells. However, the influence of hypoxia on anti-fungal immunity has been largely unknown. We evaluated the impact of hypoxia on the human anti- A. fumigatus immune response. Human monocyte-derived dendritic cells ( DCs) were stimulated in vitro with germ tubes of A. fumigatus under normoxia or hypoxia (1% O2), followed by analysis of DC viability, maturation and cytokine release. While DC viability was unaffected, hypoxia attenuated cytokine release from DCs and maturation of DCs upon stimulation with A. fumigatus. These data suggest that hypoxia at the site of A. fumigatus infection inhibits full activation and function of human DCs. Thereby, this study identified hypoxia as a crucial immune-modulating factor in the human anti-fungal immune response that might influence the course and outcome of IPA in immunocompromised patients. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
12. Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface.
- Author
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Morton, Charles Oliver, Fliesser, Mirjam, Dittrich, Marcus, Mueller, Tobias, Bauer, Ruth, Kneitz, Susanne, Hope, William, Rogers, Thomas Richard, Einsele, Hermann, and Loeffler, Juergen
- Subjects
- *
FUNGAL gene expression , *ASPERGILLUS fumigatus , *ENDOTHELIUM , *ASPERGILLOSIS , *EPITHELIAL cells , *IMMUNE response , *MICROARRAY technology - Abstract
The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
13. Fever-range temperature modulates activation and function of human dendritic cells stimulated with the pathogenic mould Aspergillus fumigatus.
- Author
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Semmlinger, Anna, Fliesser, Mirjam, Waaga-Gasser, Ana Maria, Dragan, Mariola, Morton, C. Oliver, Einsele, Hermann, and Loeffler, Juergen
- Abstract
In immunocompromised patients, invasive aspergillosis (IA) is the most frequent disease caused by the pathogenic mould Aspergillus fumigatus. Fever is one of the most common yet nonspecific clinical symptoms of IA. To evaluate the role of hyperthermia in the innate immune response to A. fumigatus in vitro, human monocyte-derived dendritic cells (DCs) were stimulated with germ tubes of A. fumigatus or the fungal cell wall component zymosan at 37°C or 40°C, followed by characterization of specific DC functions. While maturation of DCs was enhanced and DC phagocytic capacity was reduced at 40°C, we observed that DC viability and cytokine release were unaffected. Thus, our results suggest that hyperthermia has substantial impacts on DC function in vitro, which might also influence the course and outcome of IA in immunocompromised patients. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
- Full Text
- View/download PDF
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