30 results on '"Fatykhova D"'
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2. An investigation of antigenotoxic properties of plant extracts of Chelidonium majus L., Plantago major L. and Tussilago farfara L.
- Author
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Karamova, N. S., Fatykhova, D. G., Abdrakhimova, Y. R., and Il’inskaya, O. N.
- Published
- 2011
- Full Text
- View/download PDF
3. Das ex vivo Modell der humanen Lunge in der Pneumonieforschung
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Hönzke, K, additional, Fatykhova, D, additional, Tönnies, M, additional, Bauer, TT, additional, Schneider, P, additional, Neudecker, J, additional, Rückert, JC, additional, Eggeling, S, additional, Schimek, M, additional, Gruber, AD, additional, Suttorp, N, additional, Hippenstiel, S, additional, and Hocke, AC, additional
- Published
- 2019
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4. Problems of modern russian economy through the eyes of teachers and students: Results of sociological research in Russian universities
- Author
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Myuller D. and Fatykhova D.
- Subjects
State policy ,Young students ,Teachers ,Sociological research ,University community ,Socio-economic development - Abstract
The article is devoted to the results of sociological research conducted in Russian universities in December 2015 - March 2016. The aim of the study was to identify the main problems of economic development of the Russian Federation that are of interest to teachers and students. The course taken by the Russian state five years ago to ensure openness and transparency of the activities of state bodies must ensure the availability of information necessary in the process of expert and analytical work. In this regard, the survey has also set the objective to determine how the steps taken in this area have provided the necessary information for the society, including the expert community. In the process of the study we have revealed the peculiarities of perception of the Russian economy structural problems by representatives of university community (teachers and students), especially the perception by the group of officially published information, as well as we have established how the representatives of university community assess the effectiveness of policy to ensure the transparency of public authorities and common understanding the mechanisms of governance.
- Published
- 2016
5. Spatial and temporal regulation of neutrophil-attractant CXCL5/LIX in acute streptococcal pneumonia
- Author
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Berger, S, additional, Wienhold, SM, additional, Gökeri, C, additional, Behrendt, U, additional, Fatykhova, D, additional, Zscheppang, K, additional, Berg, J, additional, Gisch, N, additional, Dietert, K, additional, Doehn, JM, additional, Hocke, A, additional, Witzenrath, M, additional, and Nouailles-Kursar, G, additional
- Published
- 2017
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6. Interferons suppress IL-1beta dependent GM-CSF in post-influenza pneumococcal infection of human lungs
- Author
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Zscheppang, K, primary, Berg, J, additional, Fatykhova, D, additional, Tönnies, M, additional, Bauer, TT, additional, Schneider, P, additional, Neudecker, J, additional, Rückert, J, additional, Eggeling, S, additional, Schimek, M, additional, Gruber, A, additional, Suttorp, N, additional, Hippenstiel, S, additional, and Hocke, AC, additional
- Published
- 2016
- Full Text
- View/download PDF
7. An investigation of antigenotoxic properties of plant extracts of Chelidonium majus L., Plantago major L. and Tussilago farfara L
- Author
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Karamova N., Fatykhova D., Abdrakhimova Y., and Il'inskaya O.
- Subjects
SOS chromotest ,plant sap ,antigenotoxic effect ,Rec assay ,Plantago major L ,Chelidonium majus L ,Tussilago farfara L - Abstract
The antigenotoxic properties of the sap from three medicinal plants, the greater celandine (Chelidonium majus L.), the greater plantain (Plantago major L.), and coltsfoot (Tussilago farfara L.), were studied using two bacterial test systems (SOS chromotest and Rec assay). It was determined using the combined effect of the plant sap and model genotoxicants on the cells of test strains that the plant sap of the greater celandine reveals a dismutagenic effect decreasing the genotoxic effect of nalidixic acid in the SOS chromotest and furacilin in the Rec assay. The plants sap of the greater celandine and coltsfoot (in 1: 10 and 1: 100 dilutions) demonstrated a bioantimutagenic effect in the SOS chromotest because pre-incubation of the E. coli PQ37 cells test strain with the sap of these plants resulted in a significant decrease of the genotoxic effect of nalidixic acid. The antigenotoxic effect of the greater plantain sap was not statistically significant in both test systems. Possible mechanisms of determining the antigenotoxic properties of the plant sap from greater celandine and coltsfoot are discussed. © 2011 Pleiades Publishing, Ltd.
- Published
- 2011
8. Expression und Regulation von Pentraxin 3 bei ambulant erworbener Pneumonie
- Author
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Doehn, JM, primary, Griß, K, additional, Zahlten, J, additional, Fatykhova, D, additional, Wienhold, S, additional, Müller-Redetzky, HC, additional, Kershaw, O, additional, Gruber, AD, additional, Suttorp, N, additional, Schütte, H, additional, Hocke, AC, additional, Witzenrath, M, additional, Hippenstiel, S, additional, and CAPNETZ, Study Group, additional
- Published
- 2014
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9. Problems of determination of the performance indicators of the Russian federation state,Problemas de determinación de los indicadores de desempeño del estado de la federación Rusa
- Author
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Fatykhova, D. R., Laptev, V. V., Müller, D. G., and Uossoupov, S. R.
10. Problems of determination of the performance indicators of the Russian federation state
- Author
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Fatykhova D., Laptev V., Müller D., Uossoupov S., Fatykhova D., Laptev V., Müller D., and Uossoupov S.
- Abstract
© 2019, Universidad del Zulia. All rights reserved. The article discusses the main features of the Russian Federation state policy implementation in the field of physical culture and sports. The methodological basis of the research is the systemic and structural-functional approaches, logical and comparative methods. As a result, the absence of elaborated alternative action scenarios and options in adopted programs makes it impossible to respond flexibly and promptly change the content of state policy. In conclusion, the process of information collection and processing concerning the achievement of the values of indicators is usually not automated, which makes the process long and time-consuming.
11. Problems of modern russian economy through the eyes of teachers and students: Results of sociological research in Russian universities
- Author
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Myuller D., Fatykhova D., Myuller D., and Fatykhova D.
- Abstract
The article is devoted to the results of sociological research conducted in Russian universities in December 2015 - March 2016. The aim of the study was to identify the main problems of economic development of the Russian Federation that are of interest to teachers and students. The course taken by the Russian state five years ago to ensure openness and transparency of the activities of state bodies must ensure the availability of information necessary in the process of expert and analytical work. In this regard, the survey has also set the objective to determine how the steps taken in this area have provided the necessary information for the society, including the expert community. In the process of the study we have revealed the peculiarities of perception of the Russian economy structural problems by representatives of university community (teachers and students), especially the perception by the group of officially published information, as well as we have established how the representatives of university community assess the effectiveness of policy to ensure the transparency of public authorities and common understanding the mechanisms of governance.
12. An investigation of antigenotoxic properties of plant extracts of Chelidonium majus L., Plantago major L. and Tussilago farfara L
- Author
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Karamova N., Fatykhova D., Abdrakhimova Y., Il'inskaya O., Karamova N., Fatykhova D., Abdrakhimova Y., and Il'inskaya O.
- Abstract
The antigenotoxic properties of the sap from three medicinal plants, the greater celandine (Chelidonium majus L.), the greater plantain (Plantago major L.), and coltsfoot (Tussilago farfara L.), were studied using two bacterial test systems (SOS chromotest and Rec assay). It was determined using the combined effect of the plant sap and model genotoxicants on the cells of test strains that the plant sap of the greater celandine reveals a dismutagenic effect decreasing the genotoxic effect of nalidixic acid in the SOS chromotest and furacilin in the Rec assay. The plants sap of the greater celandine and coltsfoot (in 1: 10 and 1: 100 dilutions) demonstrated a bioantimutagenic effect in the SOS chromotest because pre-incubation of the E. coli PQ37 cells test strain with the sap of these plants resulted in a significant decrease of the genotoxic effect of nalidixic acid. The antigenotoxic effect of the greater plantain sap was not statistically significant in both test systems. Possible mechanisms of determining the antigenotoxic properties of the plant sap from greater celandine and coltsfoot are discussed. © 2011 Pleiades Publishing, Ltd.
13. Problems of modern russian economy through the eyes of teachers and students: Results of sociological research in Russian universities
- Author
-
Myuller D., Fatykhova D., Myuller D., and Fatykhova D.
- Abstract
The article is devoted to the results of sociological research conducted in Russian universities in December 2015 - March 2016. The aim of the study was to identify the main problems of economic development of the Russian Federation that are of interest to teachers and students. The course taken by the Russian state five years ago to ensure openness and transparency of the activities of state bodies must ensure the availability of information necessary in the process of expert and analytical work. In this regard, the survey has also set the objective to determine how the steps taken in this area have provided the necessary information for the society, including the expert community. In the process of the study we have revealed the peculiarities of perception of the Russian economy structural problems by representatives of university community (teachers and students), especially the perception by the group of officially published information, as well as we have established how the representatives of university community assess the effectiveness of policy to ensure the transparency of public authorities and common understanding the mechanisms of governance.
14. An investigation of antigenotoxic properties of plant extracts of Chelidonium majus L., Plantago major L. and Tussilago farfara L
- Author
-
Karamova N., Fatykhova D., Abdrakhimova Y., Il'inskaya O., Karamova N., Fatykhova D., Abdrakhimova Y., and Il'inskaya O.
- Abstract
The antigenotoxic properties of the sap from three medicinal plants, the greater celandine (Chelidonium majus L.), the greater plantain (Plantago major L.), and coltsfoot (Tussilago farfara L.), were studied using two bacterial test systems (SOS chromotest and Rec assay). It was determined using the combined effect of the plant sap and model genotoxicants on the cells of test strains that the plant sap of the greater celandine reveals a dismutagenic effect decreasing the genotoxic effect of nalidixic acid in the SOS chromotest and furacilin in the Rec assay. The plants sap of the greater celandine and coltsfoot (in 1: 10 and 1: 100 dilutions) demonstrated a bioantimutagenic effect in the SOS chromotest because pre-incubation of the E. coli PQ37 cells test strain with the sap of these plants resulted in a significant decrease of the genotoxic effect of nalidixic acid. The antigenotoxic effect of the greater plantain sap was not statistically significant in both test systems. Possible mechanisms of determining the antigenotoxic properties of the plant sap from greater celandine and coltsfoot are discussed. © 2011 Pleiades Publishing, Ltd.
15. Microenvironmental acidification by pneumococcal sugar consumption fosters barrier disruption and immune suppression in the human alveolus.
- Author
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Fatykhova D, Fritsch VN, Siebert K, Methling K, Lalk M, Busche T, Kalinowski J, Weiner J, Beule D, Bertrams W, Kohler TP, Hammerschmidt S, Löwa A, Fischer M, Mieth M, Hellwig K, Frey D, Neudecker J, Rueckert JC, Toennies M, Bauer TT, Graff M, Tran HL, Eggeling S, Gruber AD, Antelmann H, Hippenstiel S, and Hocke AC
- Abstract
Streptococcus pneumoniae ( S.p. ) is the most common causative agent of community-acquired pneumonia worldwide. A key pathogenic mechanism that exacerbates severity of disease is the disruption of the alveolar-capillary barrier. However, the specific virulence mechanisms responsible for this in the human lung are not yet fully understood.In this study, we infected living human lung tissue with S.p. and observed a significant degradation of the central junctional proteins occludin and VE-cadherin, indicating barrier disruption. Surprisingly, neither pneumolysin, bacterial hydrogen peroxide nor pro-inflammatory activation were sufficient to cause this junctional degradation. Instead, pneumococcal infection led to a significant decrease of pH (approximately 6), resulting in acidification of the alveolar microenvironment, which was linked to junctional degradation. Stabilising the pH at physiological levels during infection reversed this effect, even in a therapeutic-like approach.Further analysis of bacterial metabolites and RNA sequencing revealed sugar consumption and subsequent lactate production were the major factors contributing to bacterially induced alveolar acidification, which also hindered the release of critical immune factors.Our findings highlight bacterial metabolite-induced acidification as an independent virulence mechanism for barrier disruption and inflammatory dysregulation in pneumonia. Thus, our data suggest that strictly monitoring and buffering alveolar pH during infections caused by fermentative bacteria could serve as an adjunctive therapeutic strategy for sustaining barrier integrity and immune response., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)
- Published
- 2024
- Full Text
- View/download PDF
16. SARS-CoV-2 tropism to intestinal but not gastric epithelial cells is defined by limited ACE2 expression.
- Author
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Paužuolis M, Fatykhova D, Zühlke B, Schwecke T, Neyazi M, Samperio-Ventayol P, Aguilar C, Schlegel N, Dökel S, Ralser M, Hocke A, Krempl C, and Bartfeld S
- Subjects
- Humans, Viral Tropism, Organoids virology, Organoids metabolism, Epithelial Cells metabolism, Epithelial Cells virology, Virus Replication, Animals, Angiotensin-Converting Enzyme 2 metabolism, Angiotensin-Converting Enzyme 2 genetics, SARS-CoV-2 physiology, COVID-19 virology, COVID-19 metabolism, Intestinal Mucosa metabolism, Intestinal Mucosa virology, Gastric Mucosa metabolism, Gastric Mucosa virology
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affects the lung but can also cause gastrointestinal (GI) symptoms. In vitro experiments confirmed that SARS-CoV-2 robustly infects intestinal epithelium. However, data on infection of adult gastric epithelium are sparse and a side-by-side comparison of the infection in the major segments of the GI tract is lacking. We provide this direct comparison in organoid-derived monolayers and demonstrate that SARS-CoV-2 robustly infects intestinal epithelium, while gastric epithelium is resistant to infection. RNA sequencing and proteome analysis pointed to angiotensin-converting enzyme 2 (ACE2) as a critical factor, and, indeed, ectopic expression of ACE2 increased susceptibility of gastric organoid-derived monolayers to SARS-CoV-2. ACE2 expression pattern in GI biopsies of patients mirrors SARS-CoV-2 infection levels in monolayers. Thus, local ACE2 expression limits SARS-CoV-2 expression in the GI tract to the intestine, suggesting that the intestine, but not the stomach, is likely to be important in viral replication and possibly transmission., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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17. Correction: State-of-the-art analytical methods of viral infections in human lung organoids.
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Baumgardt M, Hülsemann M, Löwa A, Fatykhova D, Hoffmann K, Kessler M, Mieth M, Hellwig K, Frey D, Langenhagen A, Voss A, Obermayer B, Wyler E, Dökel S, Gruber AD, Tölch U, Hippenstiel S, Hocke AC, and Hönzke K
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0276115.]., (Copyright: © 2023 Baumgardt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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18. The unremarkable alveolar epithelial glycocalyx: a thorium dioxide-based electron microscopic comparison after heparinase or pneumolysin treatment.
- Author
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Timm S, Lettau M, Hegermann J, Rocha ML, Weidenfeld S, Fatykhova D, Gutbier B, Nouailles G, Lopez-Rodriguez E, Hocke A, Hippenstiel S, Witzenrath M, Kuebler WM, and Ochs M
- Subjects
- Mice, Humans, Animals, Heparin Lyase, Electrons, Glycosaminoglycans, Glycocalyx, Thorium Dioxide
- Abstract
Recent investigations analyzed in depth the biochemical and biophysical properties of the endothelial glycocalyx. In comparison, this complex cell-covering structure is largely understudied in alveolar epithelial cells. To better characterize the alveolar glycocalyx ultrastructure, unaffected versus injured human lung tissue explants and mouse lungs were analyzed by transmission electron microscopy. Lung tissue was treated with either heparinase (HEP), known to shed glycocalyx components, or pneumolysin (PLY), the exotoxin of Streptococcus pneumoniae not investigated for structural glycocalyx effects so far. Cationic colloidal thorium dioxide (cThO
2 ) particles were used for glycocalyx glycosaminoglycan visualization. The level of cThO2 particles orthogonal to apical cell membranes (≙ stained glycosaminoglycan height) of alveolar epithelial type I (AEI) and type II (AEII) cells was stereologically measured. In addition, cThO2 particle density was studied by dual-axis electron tomography (≙ stained glycosaminoglycan density in three dimensions). For untreated samples, the average cThO2 particle level was ≈ 18 nm for human AEI, ≈ 17 nm for mouse AEI, ≈ 44 nm for human AEII and ≈ 35 nm for mouse AEII. Both treatments, HEP and PLY, resulted in a significant reduction of cThO2 particle levels on human and mouse AEI and AEII. Moreover, a HEP- and PLY-associated reduction in cThO2 particle density was observed. The present study provides quantitative data on the differential glycocalyx distribution on AEI and AEII based on cThO2 and demonstrates alveolar glycocalyx shedding in response to HEP or PLY resulting in a structural reduction in both glycosaminoglycan height and density. Future studies should elucidate the underlying alveolar epithelial cell type-specific distribution of glycocalyx subcomponents for better functional understanding., (© 2023. The Author(s).)- Published
- 2023
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19. Ex vivo infection model for Francisella using human lung tissue.
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Köppen K, Fatykhova D, Holland G, Rauch J, Tappe D, Graff M, Rydzewski K, Hocke AC, Hippenstiel S, and Heuner K
- Subjects
- Animals, Humans, Rabbits, Mice, Cytokines metabolism, Lung microbiology, Chemokines metabolism, Bacterial Vaccines, Mice, Inbred C57BL, Francisella tularensis genetics, Tularemia microbiology
- Abstract
Introduction: Tularemia is mainly caused by Francisella tularensis ( Ft ) subsp. tularensis ( Ftt ) and Ft subsp. holarctica ( Ftt ) in humans and in more than 200 animal species including rabbits and hares. Human clinical manifestations depend on the route of infection and range from flu-like symptoms to severe pneumonia with a mortality rate up to 60% without treatment. So far, only 2D cell culture and animal models are used to study Francisella virulence , but the gained results are transferable to human infections only to a certain extent., Method: In this study, we firstly established an ex vivo human lung tissue infection model using different Francisella strains: Ftt Life Vaccine Strain (LVS), Ftt LVS ΔiglC, Ftt human clinical isolate A-660 and a German environmental Francisella species strain W12-1067 ( F -W12). Human lung tissue was used to determine the colony forming units and to detect infected cell types by using spectral immunofluorescence and electron microscopy. Chemokine and cytokine levels were measured in culture supernatants., Results: Only LVS and A-660 were able to grow within the human lung explants, whereas LVS ΔiglC and F -W12 did not replicate. Using human lung tissue, we observed a greater increase of bacterial load per explant for patient isolate A-660 compared to LVS, whereas a similar replication of both strains was observed in cell culture models with human macrophages. Alveolar macrophages were mainly infected in human lung tissue, but Ftt was also sporadically detected within white blood cells. Although Ftt replicated within lung tissue, an overall low induction of pro-inflammatory cytokines and chemokines was observed. A-660-infected lung explants secreted slightly less of IL-1β, MCP-1, IP-10 and IL-6 compared to Ftt LVS-infected explants, suggesting a more repressed immune response for patient isolate A-660. When LVS and A-660 were used for simultaneous co-infections, only the ex vivo model reflected the less virulent phenotype of LVS, as it was outcompeted by A-660., Conclusion: We successfully implemented an ex vivo infection model using human lung tissue for Francisella . The model delivers considerable advantages and is able to discriminate virulent Francisella from less- or non-virulent strains and can be used to investigate the role of specific virulence factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Köppen, Fatykhova, Holland, Rauch, Tappe, Graff, Rydzewski, Hocke, Hippenstiel and Heuner.)
- Published
- 2023
- Full Text
- View/download PDF
20. State-of-the-art analytical methods of viral infections in human lung organoids.
- Author
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Baumgardt M, Hülsemann M, Löwa A, Fatykhova D, Hoffmann K, Kessler M, Mieth M, Hellwig K, Frey D, Langenhagen A, Voss A, Obermayer B, Wyler E, Dökel S, Gruber AD, Tölch U, Hippenstiel S, Hocke AC, and Hönzke K
- Subjects
- Humans, SARS-CoV-2, Furin metabolism, Angiotensin-Converting Enzyme 2 metabolism, Pandemics, Lung metabolism, Organoids, COVID-19 metabolism
- Abstract
Human-based organ models can provide strong predictive value to investigate the tropism, virulence, and replication kinetics of viral pathogens. Currently, such models have received widespread attention in the study of SARS-CoV-2 causing the COVID-19 pandemic. Applicable to a large set of organoid models and viruses, we provide a step-by-step work instruction for the infection of human alveolar-like organoids with SARS-CoV-2 in this protocol collection. We also prepared a detailed description on state-of-the-art methodologies to assess the infection impact and the analysis of relevant host factors in organoids. This protocol collection consists of five different sets of protocols. Set 1 describes the protein extraction from human alveolar-like organoids and the determination of protein expression of angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and FURIN as exemplary host factors of SARS-CoV-2. Set 2 provides detailed guidance on the extraction of RNA from human alveolar-like organoids and the subsequent qPCR to quantify the expression level of ACE2, TMPRSS2, and FURIN as host factors of SARS-CoV-2 on the mRNA level. Protocol set 3 contains an in-depth explanation on how to infect human alveolar-like organoids with SARS-CoV-2 and how to quantify the viral replication by plaque assay and viral E gene-based RT-qPCR. Set 4 provides a step-by-step protocol for the isolation of single cells from infected human alveolar-like organoids for further processing in single-cell RNA sequencing or flow cytometry. Set 5 presents a detailed protocol on how to perform the fixation of human alveolar-like organoids and guides through all steps of immunohistochemistry and in situ hybridization to visualize SARS-CoV-2 and its host factors. The infection and all subsequent analytical methods have been successfully validated by biological replications with human alveolar-like organoids based on material from different donors., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Baumgardt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2022
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21. Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation.
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Erfinanda L, Zou L, Gutbier B, Kneller L, Weidenfeld S, Michalick L, Lei D, Reppe K, Teixeira Alves LG, Schneider B, Zhang Q, Li C, Fatykhova D, Schneider P, Liedtke W, Sohara E, Mitchell TJ, Gruber AD, Hocke A, Hippenstiel S, Suttorp N, Olschewski A, Mall MA, Witzenrath M, and Kuebler WM
- Subjects
- Humans, Mice, Animals, Calcium, Lung, Cystic Fibrosis Transmembrane Conductance Regulator, TRPV Cation Channels, Chlorides, Pneumonia
- Abstract
Pneumonia is the most common cause of the acute respiratory distress syndrome (ARDS). Here, we identified loss of endothelial cystic fibrosis transmembrane conductance regulator (CFTR) as an important pathomechanism leading to lung barrier failure in pneumonia-induced ARDS. CFTR was down-regulated after Streptococcus pneumoniae infection ex vivo or in vivo in human or murine lung tissue, respectively. Analysis of isolated perfused rat lungs revealed that CFTR inhibition increased endothelial permeability in parallel with intracellular chloride ion and calcium ion concentrations ([Cl
- ]i and [Ca2+ ]i ). Inhibition of the chloride ion-sensitive with-no-lysine kinase 1 (WNK1) protein with tyrphostin 47 or WNK463 replicated the effect of CFTR inhibition on endothelial permeability and endothelial [Ca2+ ]i , whereas WNK1 activation by temozolomide attenuated it. Endothelial [Ca2+ ]i transients and permeability in response to inhibition of either CFTR or WNK1 were prevented by inhibition of the cation channel transient receptor potential vanilloid 4 (TRPV4). Mice deficient in Trpv4 ( Trpv4-/- ) developed less lung edema and protein leak than their wild-type littermates after infection with S. pneumoniae . The CFTR potentiator ivacaftor prevented lung CFTR loss, edema, and protein leak after S. pneumoniae infection in wild-type mice. In conclusion, lung infection caused loss of CFTR that promoted lung edema formation through intracellular chloride ion accumulation, inhibition of WNK1, and subsequent disinhibition of TRPV4, resulting in endothelial calcium ion influx and vascular barrier failure. Ivacaftor prevented CFTR loss in the lungs of mice with pneumonia and may, therefore, represent a possible therapeutic strategy in people suffering from ARDS due to severe pneumonia.- Published
- 2022
- Full Text
- View/download PDF
22. Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages.
- Author
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Hönzke K, Obermayer B, Mache C, Fatykhova D, Kessler M, Dökel S, Wyler E, Baumgardt M, Löwa A, Hoffmann K, Graff P, Schulze J, Mieth M, Hellwig K, Demir Z, Biere B, Brunotte L, Mecate-Zambrano A, Bushe J, Dohmen M, Hinze C, Elezkurtaj S, Tönnies M, Bauer TT, Eggeling S, Tran HL, Schneider P, Neudecker J, Rückert JC, Schmidt-Ott KM, Busch J, Klauschen F, Horst D, Radbruch H, Radke J, Heppner F, Corman VM, Niemeyer D, Müller MA, Goffinet C, Mothes R, Pascual-Reguant A, Hauser AE, Beule D, Landthaler M, Ludwig S, Suttorp N, Witzenrath M, Gruber AD, Drosten C, Sander LE, Wolff T, Hippenstiel S, and Hocke AC
- Subjects
- Adult, Humans, Angiotensin-Converting Enzyme 2, Lung pathology, Macrophages, Alveolar metabolism, Peptidyl-Dipeptidase A metabolism, SARS-CoV-2, Viral Tropism, COVID-19, Influenza, Human
- Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive., Methods: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results., Results: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection., Conclusions: Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment., Competing Interests: Conflict of interest: J-C. Rückert and H. Radbruch report support from DFG RA 2491/1-1, BMBF (Defeat Pandemics). A.E. Hauser reports support from Charité – Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin, and grants from Deutsche Forschungsgemeinschaft (HA5354/10-1, TRR130,P17 and C01, HA5354/8-1). T. Wolff reports support from Federal Ministry of Education and Research (BMBF) grant 01K12006F. M. Kessler reports grants from BMBF Organo-Strat, Einstein 3R. M. Dohmen reports contracts with Max-Delbrück Center, Berlin; grants from Gender Equality Fund, Berlin Institute of Health. F. Klauschen reports consulting fees, lecture honoraria, travel support and participation on advisory boards with BMS, Novartis, Roche and Lilly, and is a co-founder of AI-BIH/Charité-Spinoff Aignostics GmbH. F. Heppner reports consulting fees, lecture honoraria, payment for expert testimony and leadership roles at Novartis, AstraZeneca and ThinkHealth Hygiene Solutions. V.M. Corman reports the following patents: 20210190797 (Methods and reagents for diagnosis of SARS-CoV-2 infection); 9841834 (Human recombinant monoclonal antibody against SARS-CoV-2 spike glycoprotein); 9909654 (A pharmaceutical combination comprising an anti-viral protonophore and a serine protease inhibitor). D. Niemeyer reports that Technische Universität Berlin, Freie Universität Berlin and Charité – Universitätsmedizin have filed a patent application for siRNAs inhibiting SARS-CoV-2 replication with D. Niemeyer as coauthor. M.A. Müller reports the following patents: 20210190797 (Methods and reagents for diagnosis of SARS-CoV-2 infection); 9841834 (Human recombinant monoclonal antibody against SARS-CoV-2 spike glycoprotein); 9909654 (A pharmaceutical combination comprising an anti-viral protonophore and a serine protease inhibitor); and has participated on an advisory board for ECDC/WHO. S. Ludwig reports consulting fees from Atriva Therapeutics GmbH, Biontec SE; and has patent PCT/EP2021/063485 pending. M. Witzenrath reports grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Stiftung, Capnetz Stiftung, International Max Planck Research School, Quark Pharma, Takeda Pharma, Noxxon, Pantherna, Silence Therapeutics, Vaxxilon, Actelion, Bayer Health Care, Biotest and Boehringer Ingelheim; consulting fees from Noxxon, Pantherna, Silence Therapeutics, Vaxxilon, Aptarion, GlaxoSmithKline, Sinoxa and Biotest; lecture honoraria from AstraZeneca, Berlin Chemie, Chiesi, Novartis, Teva, Actelion, Boehringer Ingelheim, GlaxoSmithKline, Biotest, Bayer Health Care; and has the following patents issued: EPO 12181535.1 (IL-27 for modulation of immune response in acute lung injury), WO/2010/094491 (Means for inhibiting the expression of Ang-2), DE 102020116249.9 (Camostat/Niclosamide cotreatment in SARS-CoV-2 infected human lung cells). All other authors have nothing to disclose., (Copyright ©The authors 2022.)
- Published
- 2022
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23. Human alveolar progenitors generate dual lineage bronchioalveolar organoids.
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Hoffmann K, Obermayer B, Hönzke K, Fatykhova D, Demir Z, Löwa A, Alves LGT, Wyler E, Lopez-Rodriguez E, Mieth M, Baumgardt M, Hoppe J, Firsching TC, Tönnies M, Bauer TT, Eggeling S, Tran HL, Schneider P, Neudecker J, Rückert JC, Gruber AD, Ochs M, Landthaler M, Beule D, Suttorp N, Hippenstiel S, Hocke AC, and Kessler M
- Subjects
- Cell Differentiation genetics, Glycogen Synthase Kinase 3 beta metabolism, Humans, Wnt Signaling Pathway, Lung metabolism, Organoids metabolism
- Abstract
Mechanisms of epithelial renewal in the alveolar compartment remain incompletely understood. To this end, we aimed to characterize alveolar progenitors. Single-cell RNA-sequencing (scRNA-seq) analysis of the HTII-280
+ /EpCAM+ population from adult human lung revealed subclusters enriched for adult stem cell signature (ASCS) genes. We found that alveolar progenitors in organoid culture in vitro show phenotypic lineage plasticity as they can yield alveolar or bronchial cell-type progeny. The direction of the differentiation is dependent on the presence of the GSK-3β inhibitor, CHIR99021. By RNA-seq profiling of GSK-3β knockdown organoids we identified additional candidate target genes of the inhibitor, among others FOXM1 and EGF. This gives evidence of Wnt pathway independent regulatory mechanisms of alveolar specification. Following influenza A virus (IAV) infection organoids showed a similar response as lung tissue explants which confirms their suitability for studies of sequelae of pathogen-host interaction., (© 2022. The Author(s).)- Published
- 2022
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24. Functional comparison of MERS-coronavirus lineages reveals increased replicative fitness of the recombinant lineage 5.
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Schroeder S, Mache C, Kleine-Weber H, Corman VM, Muth D, Richter A, Fatykhova D, Memish ZA, Stanifer ML, Boulant S, Gultom M, Dijkman R, Eggeling S, Hocke A, Hippenstiel S, Thiel V, Pöhlmann S, Wolff T, Müller MA, and Drosten C
- Subjects
- Animals, Camelus, Cells, Cultured, Coronavirus Infections epidemiology, Coronavirus Infections transmission, Genome, Viral, Humans, Middle East Respiratory Syndrome Coronavirus isolation & purification, Middle East Respiratory Syndrome Coronavirus pathogenicity, Phylogeny, Recombination, Genetic, Republic of Korea epidemiology, Saudi Arabia epidemiology, Virus Replication, Coronavirus Infections virology, Middle East Respiratory Syndrome Coronavirus genetics
- Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is enzootic in dromedary camels across the Middle East and Africa. Virus-induced pneumonia in humans results from animal contact, with a potential for limited onward transmission. Phenotypic changes have been suspected after a novel recombinant clade (lineage 5) caused large nosocomial outbreaks in Saudi Arabia and South Korea in 2016. However, there has been no functional assessment. Here we perform a comprehensive in vitro and ex vivo comparison of viruses from parental and recombinant virus lineages (lineage 3, n = 7; lineage 4, n = 8; lineage 5, n = 9 viruses) from Saudi Arabia, isolated immediately before and after the shift toward lineage 5. Replication of lineage 5 viruses is significantly increased. Transcriptional profiling finds reduced induction of immune genes IFNB1, CCL5, and IFNL1 in lung cells infected with lineage 5 strains. Phenotypic differences may be determined by IFN antagonism based on experiments using IFN receptor knock out and signaling inhibition. Additionally, lineage 5 is more resilient against IFN pre-treatment of Calu-3 cells (ca. 10-fold difference in replication). This phenotypic change associated with lineage 5 has remained undiscovered by viral sequence surveillance, but may be a relevant indicator of pandemic potential., (© 2021. The Author(s).)
- Published
- 2021
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25. Plasma mediators in patients with severe COVID-19 cause lung endothelial barrier failure.
- Author
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Michalick L, Weidenfeld S, Grimmer B, Fatykhova D, Solymosi PD, Behrens F, Dohmen M, Brack MC, Schulz S, Thomasch E, Simmons S, Müller-Redetzky H, Suttorp N, Kurth F, Neudecker J, Toennies M, Bauer TT, Eggeling S, Corman VM, Hocke AC, Witzenrath M, Hippenstiel S, and Kuebler WM
- Subjects
- Actins metabolism, Antigens, CD metabolism, COVID-19 blood, Cadherins metabolism, Case-Control Studies, Hospitalization, Humans, Lung metabolism, Microvessels cytology, Occludin metabolism, SARS-CoV-2, Severity of Illness Index, COVID-19 metabolism, Capillary Permeability, Electric Impedance, Endothelial Cells metabolism, Endothelium metabolism, Plasma
- Abstract
Competing Interests: Conflict of interest: S. Weidenfeld has nothing to disclose. Conflict of interest: B. Grimmer has nothing to disclose. Conflict of interest: D. Fatykhova has nothing to disclose. Conflict of interest: P.D. Solymosi has nothing to disclose. Conflict of interest: F. Behrens has nothing to disclose. Conflict of interest: M. Dohmen has nothing to disclose. Conflict of interest: M.C. Brack has nothing to disclose. Conflict of interest: S. Schulz has nothing to disclose. Conflict of interest: E. Thomasch has nothing to disclose. Conflict of interest: S. Simmons has nothing to disclose. Conflict of interest: H. Müller-Redetzky has nothing to disclose. Conflict of interest: N. Suttorp has nothing to disclose. Conflict of interest: F. Kurth has nothing to disclose. Conflict of interest: J. Neudecker has nothing to disclose. Conflict of interest: M. Toennies has nothing to disclose. Conflict of interest: T.T. Bauer has nothing to disclose. Conflict of interest: S. Eggeling has nothing to disclose. Conflict of interest: V.M. Corman has nothing to disclose. Conflict of interest: A.C. Hocke has nothing to disclose. Conflict of interest: M. Witzenrath reports grants and personal fees from Actelion, Bayer Health Care, Biotest, Boehringer Ingelheim, Noxxon, Pantherna, Silence Therapeutics and Vaxxilon, grants from Quark Pharma and Takeda Pharma, personal fees from Aptarion, AstraZeneca, Berlin Chemie, Chiesi, GlaxoSmithKline, Novartis, Sinoxa and Teva, outside the submitted work; and has a patent “Means for inhibiting the expression of ANG2 US8829179B2” issued. Conflict of interest: S. Hippenstiel has nothing to disclose. Conflict of interest: W.M. Kuebler reports grants from Ministry of Education and Research (BMBF), German Research Foundation (DFG), German Centre for Cardiovascular Research (DZHK) and Canadian Institutes for Health Resarch (CIHR), during the conduct of the study. Conflict of interest: L. Michalick has nothing to disclose.
- Published
- 2021
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26. Pneumolysin induced mitochondrial dysfunction leads to release of mitochondrial DNA.
- Author
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Nerlich A, Mieth M, Letsiou E, Fatykhova D, Zscheppang K, Imai-Matsushima A, Meyer TF, Paasch L, Mitchell TJ, Tönnies M, Bauer TT, Schneider P, Neudecker J, Rückert JC, Eggeling S, Schimek M, Witzenrath M, Suttorp N, Hippenstiel S, and Hocke AC
- Subjects
- Adenosine Triphosphate metabolism, Alveolar Epithelial Cells metabolism, Bacterial Proteins toxicity, Calcium metabolism, Cell Line, Tumor, Cells, Cultured, Humans, Membrane Potential, Mitochondrial, Mitochondria metabolism, Mitochondrial Membrane Transport Proteins metabolism, Mitochondrial Permeability Transition Pore, Alveolar Epithelial Cells drug effects, DNA, Mitochondrial metabolism, Mitochondria drug effects, Streptolysins toxicity
- Abstract
Streptococcus pneumoniae (S.pn.) is the most common bacterial pathogen causing community acquired pneumonia. The pore-forming toxin pneumolysin (PLY) is the major virulence factor of S.pn. and supposed to affect alveolar epithelial cells thereby activating the immune system by liberation of danger-associated molecular patterns (DAMP). To test this hypothesis, we established a novel live-cell imaging based assay to analyse mitochondrial function and associated release of mitochondrial DNA (mtDNA) as DAMP in real-time. We first revealed that bacterially released PLY caused significant changes of the cellular ATP homeostasis and led to morphologic alterations of mitochondria in human alveolar epithelial cells in vitro and, by use of spectral live-tissue imaging, in human alveoli. This was accompanied by strong mitochondrial calcium influx and loss of mitochondrial membrane potential resulting in opening of the mitochondrial permeability transition pore and mtDNA release without activation of intrinsic apoptosis. Moreover, our data indicate cellular mtDNA liberation via microvesicles, which may contribute to S.pn. related pro-inflammatory immune activation in the human alveolar compartment.
- Published
- 2018
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27. Tyk2 as a target for immune regulation in human viral/bacterial pneumonia.
- Author
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Berg J, Zscheppang K, Fatykhova D, Tönnies M, Bauer TT, Schneider P, Neudecker J, Rückert JC, Eggeling S, Schimek M, Gruber AD, Suttorp N, Hippenstiel S, and Hocke AC
- Subjects
- Humans, Immunity, Innate drug effects, Immunologic Factors, Influenza A virus, Influenza, Human immunology, Interleukin-1beta metabolism, Lung drug effects, Pneumonia, Bacterial immunology, Staphylococcal Infections immunology, TYK2 Kinase metabolism, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Influenza, Human drug therapy, Interferons pharmacology, Pneumonia, Bacterial drug therapy, Staphylococcal Infections drug therapy, TYK2 Kinase antagonists & inhibitors
- Abstract
The severity and lethality of influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, the mechanisms in human lung tissue that provoke this increase in fatality are unknown and therapeutic immune modulatory options are lacking.We established a human lung ex vivo co-infection model to investigate innate immune related mechanisms contributing to the susceptibility of secondary pneumococcal pneumonia.We revealed that type I and III interferon (IFN) inhibits Streptococcus pneumoniae -induced interleukin (IL)-1β release. The lack of IL-1β resulted in the repression of bacterially induced granulocyte-macrophage colony-stimulating factor (GM-CSF) liberation. Specific inhibition of IFN receptor I and III-associated tyrosine kinase 2 (Tyk2) completely restored the S. pneumoniae -induced IL-1β-GM-CSF axis, leading to a reduction of bacterial growth. A preceding IAV infection of the human alveolus leads to a type I and III IFN-dependent blockade of the early cytokines IL-1β and GM-CSF, which are key for orchestrating an adequate innate immune response against bacteria. Their virally induced suppression may result in impaired bacterial clearance and alveolar repair.Pharmacological inhibition of Tyk2 might be a new treatment option to sustain beneficial endogenous GM-CSF levels in IAV-associated secondary bacterial pneumonia., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)
- Published
- 2017
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28. Localization and pneumococcal alteration of junction proteins in the human alveolar-capillary compartment.
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Peter A, Fatykhova D, Kershaw O, Gruber AD, Rueckert J, Neudecker J, Toennies M, Bauer TT, Schneider P, Schimek M, Eggeling S, Suttorp N, Hocke AC, and Hippenstiel S
- Subjects
- Humans, Persistent Fetal Circulation Syndrome microbiology, Pneumococcal Infections microbiology, Pulmonary Alveoli metabolism, Pulmonary Alveoli microbiology, Streptococcus pneumoniae, Cadherins metabolism, Persistent Fetal Circulation Syndrome metabolism, Pneumococcal Infections metabolism, Pulmonary Alveoli abnormalities
- Abstract
Loss of alveolar barrier function with subsequent respiratory failure is a hallmark of severe pneumonia. Although junctions between endo- and epithelial cells regulate paracellular fluid flux, little is known about their composition and regulation in the human alveolar compartment. High autofluorescence of human lung tissue in particular complicates the determination of subcellular protein localization. By comparing conventional channel mode confocal imaging with spectral imaging and linear unmixing, we demonstrate that background fluorescent spectra and fluorophore signals could be rigorously separated resulting in complete recovery of the specific signal at a high signal-to-noise ratio. Using this technique and Western blotting, we show the expression patterns of tight junction proteins occludin, ZO-1 as well as claudin-3, -4, -5 and -18 and adherence junction protein VE-cadherin in naive or Streptococcus pneumoniae-infected human lung tissue. In uninfected tissues, occludin and ZO-1 formed band-like structures in alveolar epithelial cells type I (AEC I), alveolar epithelial cells type II (AEC II) and lung capillaries, whereas claudin-3, -4 and -18 were visualised in AEC II. Claudin-5 was detected in the endothelium only. Claudin-3, -5, -18 displayed continuous band-like structures, while claudin-4 showed a dot-like expression. Pneumococcal infection reduced alveolar occludin, ZO-1, claudin-5 and VE-cadherin but did not change the presence of claudin-3, -4 and -18. Spectral confocal microscopy allows for the subcellular structural analysis of proteins in highly autofluorescent human lung tissue. The thereby observed deterioration of lung alveolar junctional organisation gives a structural explanation for alveolar barrier disruption in severe pneumococcal pneumonia.
- Published
- 2017
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29. Serotype 1 and 8 Pneumococci Evade Sensing by Inflammasomes in Human Lung Tissue.
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Fatykhova D, Rabes A, Machnik C, Guruprasad K, Pache F, Berg J, Toennies M, Bauer TT, Schneider P, Schimek M, Eggeling S, Mitchell TJ, Mitchell AM, Hilker R, Hain T, Suttorp N, Hippenstiel S, Hocke AC, and Opitz B
- Subjects
- Bacterial Proteins metabolism, Caspase 1 metabolism, Hemolysis, Humans, Interleukin-1beta biosynthesis, Lung cytology, Lung immunology, Species Specificity, Streptococcus pneumoniae classification, Streptococcus pneumoniae immunology, Streptococcus pneumoniae metabolism, Streptolysins metabolism, Inflammasomes metabolism, Lung metabolism, Lung microbiology, Streptococcus pneumoniae physiology
- Abstract
Streptococcus pneumoniae is a major cause of pneumonia, sepsis and meningitis. The pore-forming toxin pneumolysin is a key virulence factor of S. pneumoniae, which can be sensed by the NLRP3 inflammasome. Among the over 90 serotypes, serotype 1 pneumococci (particularly MLST306) have emerged across the globe as a major cause of invasive disease. The cause for its particularity is, however, incompletely understood. We therefore examined pneumococcal infection in human cells and a human lung organ culture system mimicking infection of the lower respiratory tract. We demonstrate that different pneumococcal serotypes differentially activate inflammasome-dependent IL-1β production in human lung tissue and cells. Whereas serotype 2, 3, 6B, 9N pneumococci expressing fully haemolytic pneumolysins activate NLRP3 inflammasome-dependent responses, serotype 1 and 8 strains expressing non-haemolytic toxins are poor activators of IL-1β production. Accordingly, purified haemolytic pneumolysin but not serotype 1-associated non-haemolytic toxin activates strong IL-1β production in human lungs. Our data suggest that the evasion of inflammasome-dependent innate immune responses by serotype 1 pneumococci might contribute to their ability to cause invasive diseases in humans.
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- 2015
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30. Streptococcus pneumoniae-induced regulation of cyclooxygenase-2 in human lung tissue.
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Szymanski KV, Toennies M, Becher A, Fatykhova D, N'Guessan PD, Gutbier B, Klauschen F, Neuschaefer-Rube F, Schneider P, Rueckert J, Neudecker J, Bauer TT, Dalhoff K, Drömann D, Gruber AD, Kershaw O, Temmesfeld-Wollbrueck B, Suttorp N, Hippenstiel S, and Hocke AC
- Subjects
- Colony-Forming Units Assay, Dinoprostone metabolism, Epithelial Cells microbiology, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Profiling, Humans, Immunohistochemistry methods, Inflammation, MAP Kinase Signaling System, Microscopy, Fluorescence methods, Pneumococcal Infections enzymology, Prostaglandins metabolism, Pulmonary Alveoli microbiology, Cyclooxygenase 2 metabolism, Gene Expression Regulation, Bacterial, Gene Expression Regulation, Enzymologic, Lung enzymology, Lung microbiology, Pneumococcal Infections microbiology, Streptococcus pneumoniae metabolism
- Abstract
The majority of cases of community-acquired pneumonia are caused by Streptococcus pneumoniae and most studies on pneumococcal host interaction are based on cell culture or animal experiments. Thus, little is known about infections in human lung tissue. Cyclooxygenase-2 and its metabolites play an important regulatory role in lung inflammation. Therefore, we established a pneumococcal infection model on human lung tissue demonstrating mitogen-activated protein kinase (MAPK)-dependent induction of cyclooxygenase-2 and its related metabolites. In addition to alveolar macrophages and the vascular endothelium, cyclooxygenase-2 was upregulated in alveolar type II but not type I epithelial cells, which was confirmed in lungs of patients suffering from acute pneumonia. Moreover, we demonstrated the expression profile of all four E prostanoid receptors at the mRNA level and showed functionality of the E prostanoid(4) receptor by cyclic adenosine monophosphate production. Additionally, in comparison to previous studies, cyclooxygenase-2/prostaglandin E(2) related pro- and anti-inflammatory mediator regulation was partly confirmed in human lung tissue after pneumococcal infection. Overall, cell type-specific and MAPK-dependent cyclooxygenase-2 expression and prostaglandin E(2) formation in human lung tissue may play an important role in the early phase of pneumococcal infections.
- Published
- 2012
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