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Article ; Online: Infection of Human Precision-Cut Lung Slices with the Influenza Virus.

Sewald, Katherina / Danov, Olga

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2506, Page(s) 119–134

Abstract: Viral infections are common causes of asthma exacerbations. To model these processes ex vivo, human precision-cut lung slices (PCLSs) can be used. Here we describe the infection of human PCLSs with the human influenza virus. We then provide methods to ... ...

Abstract	Viral infections are common causes of asthma exacerbations. To model these processes ex vivo, human precision-cut lung slices (PCLSs) can be used. Here we describe the infection of human PCLSs with the human influenza virus. We then provide methods to quantify the virus and reveal its localization within infected PCLSs and study consequences of infection, including cell death and production of cytokines, chemokine, and mucus. We also describe the stimulation of PCLSs with immune mediators such as pro-inflammatory tumor necrosis factor α (TNF-α). These models are useful to investigate mechanisms of virally induced asthma exacerbations and study modes of action and efficacy of antiviral and/or anti-inflammatory drugs.
MeSH term(s)	Antiviral Agents/pharmacology ; Asthma/drug therapy ; Cytokines/metabolism ; Humans ; Influenza A Virus, H1N1 Subtype ; Influenza, Human ; Lung/metabolism ; Orthomyxoviridae Infections/drug therapy
Chemical Substances	Antiviral Agents ; Cytokines
Language	English
Publishing date	2022-06-30
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2364-0_9
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Article ; Online: A modified protocol for successful miRNA profiling in human precision-cut lung slices (PCLS).

Niehof, Monika / Reamon-Buettner, Stella Marie / Danov, Olga / Hansen, Tanja / Sewald, Katherina

BMC research notes

2021 Volume 14, Issue 1, Page(s) 255

Abstract: Objective: Human precision cut lung slices (PCLS) are widely used as an ex vivo model system for drug discovery and development of new therapies. PCLS reflect the functional heterogeneity of lung tissue and possess relevant lung cell types. We thus ... ...

Abstract	Objective: Human precision cut lung slices (PCLS) are widely used as an ex vivo model system for drug discovery and development of new therapies. PCLS reflect the functional heterogeneity of lung tissue and possess relevant lung cell types. We thus determined the use of PCLS in studying non-coding RNAs notably miRNAs, which are important gene regulatory molecules. Since miRNAs play key role as mediators of respiratory diseases, they can serve as valuable prognostic or diagnostic biomarkers, and in therapeutic interventions, of lung diseases. A technical limitation though is the vast amount of agarose in PCLS which impedes (mi)RNA extraction by standard procedures. Here we modified our recently published protocol for RNA isolation from PCLS to enable miRNA readouts. Results: The modified method relies on the separation of lysis and precipitation steps, and a clean-up procedure with specific magnetic beads. We obtained successfully quality miRNA amenable for downstream applications such as RTqPCR and whole transcriptome miRNA analysis. Comparison of miRNA profiles in PCLS with published data from human lung, identified all important miRNAs regulated in IPF, COPD, asthma or lung cancer. Therefore, this shows suitability of the method for analyzing miRNA targets and biomarkers in the valuable human PCLS model.
MeSH term(s)	Gene Expression Profiling ; Humans ; Lung ; Lung Diseases ; Lung Neoplasms ; MicroRNAs
Chemical Substances	MicroRNAs
Language	English
Publishing date	2021-07-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2413336-X
ISSN	1756-0500 ; 1756-0500
ISSN (online)	1756-0500
ISSN	1756-0500
DOI	10.1186/s13104-021-05674-w
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Article ; Online: The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue.

Zimniak, Melissa / Kirschner, Luisa / Hilpert, Helen / Geiger, Nina / Danov, Olga / Oberwinkler, Heike / Steinke, Maria / Sewald, Katherina / Seibel, Jürgen / Bodem, Jochen

Scientific reports

2021 Volume 11, Issue 1, Page(s) 5890

Abstract: To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. ... ...

Abstract	To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8 µg/ml significantly in these screenings, and the EC50 was determined with 387 ng/ml. Furthermore, Fluoxetine reduced viral infectivity in precision-cut human lung slices showing its activity in relevant human tissue targeted in severe infections. Fluoxetine treatment resulted in a decrease in viral protein expression. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus, indicating that the R-form might specifically be used for SARS-CoV-2 treatment. Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. Moreover, since it is known that Fluoxetine inhibits cytokine release, we see the role of Fluoxetine in the treatment of SARS-CoV-2 infected patients of risk groups.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; COVID-19/virology ; Cell Line ; Cells, Cultured ; Fluoxetine/pharmacology ; Fluoxetine/therapeutic use ; Humans ; Lung/drug effects ; Lung/pathology ; Lung/virology ; SARS-CoV-2/drug effects ; Serotonin Uptake Inhibitors/pharmacology ; Serotonin Uptake Inhibitors/therapeutic use ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Serotonin Uptake Inhibitors ; Fluoxetine (01K63SUP8D)
Language	English
Publishing date	2021-03-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-85049-0
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Article ; Online: Rupintrivir reduces RV-induced T

Danov, Olga / Lasswitz, Lisa / Obernolte, Helena / Hesse, Christina / Braun, Armin / Wronski, Sabine / Sewald, Katherina

Respiratory research

2019 Volume 20, Issue 1, Page(s) 228

Abstract: Background: Antiviral drugs such as rupintrivir may have an immune-modulatory effect in experimentally induced allergic asthma with subsequent RV infection. We infected lung slices of house-dust mite (HDM)-sensitized asthmatic mice ex vivo with human ... ...

Abstract	Background: Antiviral drugs such as rupintrivir may have an immune-modulatory effect in experimentally induced allergic asthma with subsequent RV infection. We infected lung slices of house-dust mite (HDM)-sensitized asthmatic mice ex vivo with human rhinovirus (RV) and investigated the effect of the antiviral drug rupintrivir on RV-induced cytokine response in lung tissue of HDM-sensitized mice ex vivo. Methods: Mice were sensitized with HDM. Precision-cut lung slices (PCLS) were prepared from HDM-sensitized or non-sensitized mice. Lung slices were infected ex vivo with RV or RV together with rupintrivir. Modulation of immune responses was evaluated by cytokine secretion 48 h post infection. Results: In vivo HDM sensitization resulted in a T Conclusions: In summary, this study demonstrates that treatment with rupintrivir influences virus-induced IL-4 and IL-6 cytokine release under experimental conditions ex vivo.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Cytokines/antagonists & inhibitors ; Cytokines/immunology ; Female ; Interleukin-4/antagonists & inhibitors ; Interleukin-4/immunology ; Isoxazoles/pharmacology ; Lung/drug effects ; Lung/immunology ; Mice ; Mice, Inbred BALB C ; Organ Culture Techniques ; Pyroglyphidae/immunology ; Pyrrolidinones/pharmacology ; Rhinovirus ; Th2 Cells/drug effects ; Th2 Cells/immunology
Chemical Substances	Antiviral Agents ; Cytokines ; Isoxazoles ; Pyrrolidinones ; Interleukin-4 (207137-56-2) ; rupintrivir (RGE5K1Q5QW)
Language	English
Publishing date	2019-10-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-9921
ISSN (online)	1465-993X
ISSN	1465-9921
DOI	10.1186/s12931-019-1175-y
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Article ; Online: Competitive fitness of

Cramer, Nina / Nawrot, Marie Luise / Wege, Lion / Dorda, Marie / Sommer, Charline / Danov, Olga / Wronski, Sabine / Braun, Armin / Jonigk, Danny / Fischer, Sebastian / Munder, Antje / Tümmler, Burkhard

Frontiers in cellular and infection microbiology

2022 Volume 12, Page(s) 992214

Abstract: Chronic respiratory infections with the gram-negative ... ...

Abstract	Chronic respiratory infections with the gram-negative bacterium
MeSH term(s)	Animals ; Cystic Fibrosis/complications ; Cystic Fibrosis/microbiology ; Humans ; Lung/microbiology ; Mice ; Pseudomonas Infections/microbiology ; Pseudomonas aeruginosa/genetics
Language	English
Publishing date	2022-08-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2022.992214
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Article ; Online: Cyclosporin A Reveals Potent Antiviral Effects in Preclinical Models of SARS-CoV-2 Infection.

Sauerhering, Lucie / Kuznetsova, Irina / Kupke, Alexandra / Meier, Lars / Halwe, Sandro / Rohde, Cornelius / Schmidt, Jörg / Morty, Rory E / Danov, Olga / Braun, Armin / Vadász, István / Becker, Stephan / Herold, Susanne

American journal of respiratory and critical care medicine

2022 Volume 205, Issue 8, Page(s) 964–968

MeSH term(s)	Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; Cyclosporine/pharmacology ; Cyclosporine/therapeutic use ; Drug Evaluation, Preclinical ; Humans ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; Cyclosporine (83HN0GTJ6D)
Language	English
Publishing date	2022-04-10
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202108-1830LE
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Article: Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties.

Hempel, Tim / Elez, Katarina / Krüger, Nadine / Raich, Lluís / Shrimp, Jonathan H / Danov, Olga / Jonigk, Danny / Braun, Armin / Shen, Min / Hall, Matthew D / Pöhlmann, Stefan / Hoffmann, Markus / Noé, Frank

Chemical science

2021 Volume 12, Issue 38, Page(s) 12600–12609

Abstract: SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host cell proteins for viral entry into human lung cells. One of them, the protease TMPRSS2, is required to activate the viral spike protein (S). Even though two inhibitors, camostat and nafamostat, ...

Abstract	SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host cell proteins for viral entry into human lung cells. One of them, the protease TMPRSS2, is required to activate the viral spike protein (S). Even though two inhibitors, camostat and nafamostat, are known to inhibit TMPRSS2 and block cell entry of SARS-CoV-2, finding further potent therapeutic options is still an important task. In this study, we report that a late-stage drug candidate, otamixaban, inhibits SARS-CoV-2 cell entry. We show that otamixaban suppresses TMPRSS2 activity and SARS-CoV-2 infection of a human lung cell line, although with lower potency than camostat or nafamostat. In contrast, otamixaban inhibits SARS-CoV-2 infection of precision cut lung slices with the same potency as camostat. Furthermore, we report that otamixaban's potency can be significantly enhanced by (sub-) nanomolar nafamostat or camostat supplementation. Dominant molecular TMPRSS2-otamixaban interactions are assessed by extensive 109 μs of atomistic molecular dynamics simulations. Our findings suggest that combinations of otamixaban with supplemental camostat or nafamostat are a promising option for the treatment of COVID-19.
Language	English
Publishing date	2021-08-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d1sc01494c
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Article ; Online: Transcriptomic Analysis Reveals Priming of The Host Antiviral Interferon Signaling Pathway by Bronchobini

Reamon-Buettner, Stella Marie / Niehof, Monika / Hirth, Natalie / Danov, Olga / Obernolte, Helena / Braun, Armin / Warnecke, Jürgen / Sewald, Katherina / Wronski, Sabine

International journal of molecular sciences

2019 Volume 20, Issue 9

Abstract: Rhinovirus (RV) is the predominant virus causing respiratory tract infections. ... ...

Abstract	Rhinovirus (RV) is the predominant virus causing respiratory tract infections. Bronchobini
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Female ; Interferon Inducers/pharmacology ; Interferon Inducers/therapeutic use ; Interferons/metabolism ; Lung/drug effects ; Lung/metabolism ; Lung/virology ; Mice ; Mice, Inbred BALB C ; Picornaviridae Infections/drug therapy ; Picornaviridae Infections/immunology ; Picornaviridae Infections/virology ; Plant Extracts/pharmacology ; Plant Extracts/therapeutic use ; Rhinovirus/drug effects ; Rhinovirus/pathogenicity ; Signal Transduction ; Transcriptome
Chemical Substances	Antiviral Agents ; Interferon Inducers ; Plant Extracts ; Interferons (9008-11-1)
Language	English
Publishing date	2019-05-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20092242
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Article ; Online: Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis.

Bierwagen, Jeff / Wiegand, Marie / Laakmann, Katrin / Danov, Olga / Limburg, Hannah / Herbel, Stefanie Muriel / Heimerl, Thomas / Dorna, Jens / Jonigk, Danny / Preußer, Christian / Bertrams, Wilhelm / Braun, Armin / Sewald, Katherina / Schulte, Leon N / Bauer, Stefan / Pogge von Strandmann, Elke / Böttcher-Friebertshäuser, Eva / Schmeck, Bernd / Jung, Anna Lena

Cell communication and signaling : CCS

2023 Volume 21, Issue 1, Page(s) 65

Abstract: Gram-negative bacteria naturally secrete nano-sized outer membrane vesicles (OMVs), which are important mediators of communication and pathogenesis. OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune ... ...

Abstract	Gram-negative bacteria naturally secrete nano-sized outer membrane vesicles (OMVs), which are important mediators of communication and pathogenesis. OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune cells, alveolar macrophages are located at the air-tissue interface where they comprise the first line of defence against inhaled microorganisms and particles. To date, little is known about the interplay between alveolar macrophages and OMVs from pathogenic bacteria. The immune response to OMVs and underlying mechanisms are still elusive. Here, we investigated the response of primary human macrophages to bacterial vesicles (Legionella pneumophila, Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, Streptococcus pneumoniae) and observed comparable NF-κB activation across all tested vesicles. In contrast, we describe differential type I IFN signalling with prolonged STAT1 phosphorylation and strong Mx1 induction, blocking influenza A virus replication only for Klebsiella, E.coli and Salmonella OMVs. OMV-induced antiviral effects were less pronounced for endotoxin-free Clear coli OMVs and Polymyxin-treated OMVs. LPS stimulation could not mimic this antiviral status, while TRIF knockout abrogated it. Importantly, supernatant from OMV-treated macrophages induced an antiviral response in alveolar epithelial cells (AEC), suggesting OMV-induced intercellular communication. Finally, results were validated in an ex vivo infection model with primary human lung tissue. In conclusion, Klebsiella, E.coli and Salmonella OMVs induce antiviral immunity in macrophages via TLR4-TRIF-signaling to reduce viral replication in macrophages, AECs and lung tissue. These gram-negative bacteria induce antiviral immunity in the lung through OMVs, with a potential decisive and tremendous impact on bacterial and viral coinfection outcome. Video Abstract.
MeSH term(s)	Humans ; Adaptor Proteins, Vesicular Transport ; Escherichia coli ; Extracellular Vesicles ; Macrophages ; Toll-Like Receptor 4 ; Virus Replication
Chemical Substances	Adaptor Proteins, Vesicular Transport ; TLR4 protein, human ; Toll-Like Receptor 4 ; TICAM1 protein, human
Language	English
Publishing date	2023-03-28
Publishing country	England
Document type	Video-Audio Media ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-023-01086-4
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Article ; Online: TMPRSS11A activates the influenza A virus hemagglutinin and the MERS coronavirus spike protein and is insensitive against blockade by HAI-1.

Zmora, Pawel / Hoffmann, Markus / Kollmus, Heike / Moldenhauer, Anna-Sophie / Danov, Olga / Braun, Armin / Winkler, Michael / Schughart, Klaus / Pöhlmann, Stefan

The Journal of biological chemistry

2018 Volume 293, Issue 36, Page(s) 13863–13873

Abstract: The influenza virus hemagglutinin (HA) facilitates viral entry into target cells. Cleavage of HA by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential targets for antiviral intervention. The type II ... ...

Abstract	The influenza virus hemagglutinin (HA) facilitates viral entry into target cells. Cleavage of HA by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease (TTSP) TMPRSS2 has been identified as an HA activator in cell culture and in the infected host. However, it is less clear whether TMPRSS2-related enzymes can also activate HA for spread in target cells. Moreover, the activity of cellular serine protease inhibitors against HA-activating TTSPs is poorly understood. Here, we show that TMPRSS11A, another member of the TTSP family, cleaves and activates the influenza A virus (FLUAV) HA and the Middle East respiratory syndrome coronavirus spike protein (MERS-S). Moreover, we demonstrate that TMPRSS11A is expressed in murine tracheal epithelium, which is a target of FLUAV infection, and in human trachea, suggesting that the protease could support FLUAV spread in patients. Finally, we show that HA activation by the TMPRSS11A-related enzymes human airway tryptase and DESC1, but not TMPRSS11A itself, is blocked by the cellular serine protease inhibitor hepatocyte growth factor activator inhibitor type-1 (HAI-1). Our results suggest that TMPRSS11A could promote FLUAV spread in target cells and that HA-activating TTSPs exhibit differential sensitivity to blockade by cellular serine protease inhibitors.
MeSH term(s)	Animals ; Hemagglutinin Glycoproteins, Influenza Virus/metabolism ; Hemagglutinins/metabolism ; Humans ; Influenza A virus/growth & development ; Membrane Glycoproteins ; Membrane Proteins/metabolism ; Mice ; Proteinase Inhibitory Proteins, Secretory/pharmacology ; Serine Endopeptidases/metabolism ; Serine Proteases/metabolism ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization
Chemical Substances	Hemagglutinin Glycoproteins, Influenza Virus ; Hemagglutinins ; Membrane Glycoproteins ; Membrane Proteins ; Proteinase Inhibitory Proteins, Secretory ; SPINT1 protein, human ; Spike Glycoprotein, Coronavirus ; Spint1 protein, mouse ; Serine Proteases (EC 3.4.-) ; TMPRSS11A protein, mouse (EC 3.4.-) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Keywords	covid19
Language	English
Publishing date	2018-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA118.001273
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