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Extracellular Vesicle Associated miRNAs Regulate Signaling Pathways Involved in COVID-19 Pneumonia and the Progression to Severe Acute Respiratory Corona Virus-2 Syndrome

BACKGROUND: Extracellular vesicles (EVs) are mediators of cell-to-cell communication in inflammatory lung diseases. They function as carriers for miRNAs which regulate mRNA transcripts and signaling pathways after uptake into recipient cells. We investigated whether miRNAs associated with circulatin...

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Autores principales: Meidert, Agnes S., Hermann, Stefanie, Brandes, Florian, Kirchner, Benedikt, Buschmann, Dominik, Billaud, Jean-Noël, Klein, Matthias, Lindemann, Anja, Aue, Elisa, Schelling, Gustav, Pfaffl, Michael W., Reithmair, Marlene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8696174/
https://www.ncbi.nlm.nih.gov/pubmed/34956213
http://dx.doi.org/10.3389/fimmu.2021.784028
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author Meidert, Agnes S.
Hermann, Stefanie
Brandes, Florian
Kirchner, Benedikt
Buschmann, Dominik
Billaud, Jean-Noël
Klein, Matthias
Lindemann, Anja
Aue, Elisa
Schelling, Gustav
Pfaffl, Michael W.
Reithmair, Marlene
author_facet Meidert, Agnes S.
Hermann, Stefanie
Brandes, Florian
Kirchner, Benedikt
Buschmann, Dominik
Billaud, Jean-Noël
Klein, Matthias
Lindemann, Anja
Aue, Elisa
Schelling, Gustav
Pfaffl, Michael W.
Reithmair, Marlene
author_sort Meidert, Agnes S.
collection PubMed
description BACKGROUND: Extracellular vesicles (EVs) are mediators of cell-to-cell communication in inflammatory lung diseases. They function as carriers for miRNAs which regulate mRNA transcripts and signaling pathways after uptake into recipient cells. We investigated whether miRNAs associated with circulating EVs regulate immunologic processes in COVID-19. METHODS: We prospectively studied 20 symptomatic patients with COVID-19 pneumonia, 20 mechanically ventilated patients with severe COVID-19 (severe acute respiratory corona virus-2 syndrome, ARDS) and 20 healthy controls. EVs were isolated by precipitation, total RNA was extracted, profiled by small RNA sequencing and evaluated by differential gene expression analysis (DGE). Differentially regulated miRNAs between groups were bioinformatically analyzed, mRNA target transcripts identified and signaling networks constructed, thereby comparing COVID-19 pneumonia to the healthy state and pneumonia to severe COVID-19 ARDS. RESULTS: DGE revealed 43 significantly and differentially expressed miRNAs (25 downregulated) in COVID-19 pneumonia when compared to controls, and 20 miRNAs (15 downregulated) in COVID-19 ARDS patients in comparison to those with COVID-19 pneumonia. Network analysis for comparison of COVID-19 pneumonia to healthy controls showed upregulated miR-3168 (log2FC=2.28, p(adjusted)<0.001), among others, targeting interleukin-6 (IL6) (25.1, 15.2 - 88.2 pg/ml in COVID-19 pneumonia) and OR52N2, an olfactory smell receptor in the nasal epithelium. In contrast, miR-3168 was significantly downregulated in COVID-19 ARDS (log2FC=-2.13, p(adjusted)=0.003) and targeted interleukin-8 (CXCL8) in a completely activated network. Toll-like receptor 4 (TLR4) was inhibited in COVID-19 pneumonia by miR-146a-5p and upregulated in ARDS by let-7e-5p. CONCLUSION: EV-derived miRNAs might have important regulative functions in the pathophysiology of COVID-19: CXCL8 regulates neutrophil recruitment into the lung causing epithelial damage whereas activated TLR4, to which SARS-CoV-2 spike protein binds strongly, increases cell surface ACE2 expression and destroys type II alveolar cells that secrete pulmonary surfactants; both resulting in pulmonary-capillary leakage and ARDS. These miRNAs may serve as biomarkers or as possible therapeutic targets.
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spelling pubmed-86961742021-12-24 Extracellular Vesicle Associated miRNAs Regulate Signaling Pathways Involved in COVID-19 Pneumonia and the Progression to Severe Acute Respiratory Corona Virus-2 Syndrome Meidert, Agnes S. Hermann, Stefanie Brandes, Florian Kirchner, Benedikt Buschmann, Dominik Billaud, Jean-Noël Klein, Matthias Lindemann, Anja Aue, Elisa Schelling, Gustav Pfaffl, Michael W. Reithmair, Marlene Front Immunol Immunology BACKGROUND: Extracellular vesicles (EVs) are mediators of cell-to-cell communication in inflammatory lung diseases. They function as carriers for miRNAs which regulate mRNA transcripts and signaling pathways after uptake into recipient cells. We investigated whether miRNAs associated with circulating EVs regulate immunologic processes in COVID-19. METHODS: We prospectively studied 20 symptomatic patients with COVID-19 pneumonia, 20 mechanically ventilated patients with severe COVID-19 (severe acute respiratory corona virus-2 syndrome, ARDS) and 20 healthy controls. EVs were isolated by precipitation, total RNA was extracted, profiled by small RNA sequencing and evaluated by differential gene expression analysis (DGE). Differentially regulated miRNAs between groups were bioinformatically analyzed, mRNA target transcripts identified and signaling networks constructed, thereby comparing COVID-19 pneumonia to the healthy state and pneumonia to severe COVID-19 ARDS. RESULTS: DGE revealed 43 significantly and differentially expressed miRNAs (25 downregulated) in COVID-19 pneumonia when compared to controls, and 20 miRNAs (15 downregulated) in COVID-19 ARDS patients in comparison to those with COVID-19 pneumonia. Network analysis for comparison of COVID-19 pneumonia to healthy controls showed upregulated miR-3168 (log2FC=2.28, p(adjusted)<0.001), among others, targeting interleukin-6 (IL6) (25.1, 15.2 - 88.2 pg/ml in COVID-19 pneumonia) and OR52N2, an olfactory smell receptor in the nasal epithelium. In contrast, miR-3168 was significantly downregulated in COVID-19 ARDS (log2FC=-2.13, p(adjusted)=0.003) and targeted interleukin-8 (CXCL8) in a completely activated network. Toll-like receptor 4 (TLR4) was inhibited in COVID-19 pneumonia by miR-146a-5p and upregulated in ARDS by let-7e-5p. CONCLUSION: EV-derived miRNAs might have important regulative functions in the pathophysiology of COVID-19: CXCL8 regulates neutrophil recruitment into the lung causing epithelial damage whereas activated TLR4, to which SARS-CoV-2 spike protein binds strongly, increases cell surface ACE2 expression and destroys type II alveolar cells that secrete pulmonary surfactants; both resulting in pulmonary-capillary leakage and ARDS. These miRNAs may serve as biomarkers or as possible therapeutic targets. Frontiers Media S.A. 2021-12-09 /pmc/articles/PMC8696174/ /pubmed/34956213 http://dx.doi.org/10.3389/fimmu.2021.784028 Text en Copyright © 2021 Meidert, Hermann, Brandes, Kirchner, Buschmann, Billaud, Klein, Lindemann, Aue, Schelling, Pfaffl and Reithmair https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Meidert, Agnes S.
Hermann, Stefanie
Brandes, Florian
Kirchner, Benedikt
Buschmann, Dominik
Billaud, Jean-Noël
Klein, Matthias
Lindemann, Anja
Aue, Elisa
Schelling, Gustav
Pfaffl, Michael W.
Reithmair, Marlene
Extracellular Vesicle Associated miRNAs Regulate Signaling Pathways Involved in COVID-19 Pneumonia and the Progression to Severe Acute Respiratory Corona Virus-2 Syndrome
title Extracellular Vesicle Associated miRNAs Regulate Signaling Pathways Involved in COVID-19 Pneumonia and the Progression to Severe Acute Respiratory Corona Virus-2 Syndrome
title_full Extracellular Vesicle Associated miRNAs Regulate Signaling Pathways Involved in COVID-19 Pneumonia and the Progression to Severe Acute Respiratory Corona Virus-2 Syndrome
title_fullStr Extracellular Vesicle Associated miRNAs Regulate Signaling Pathways Involved in COVID-19 Pneumonia and the Progression to Severe Acute Respiratory Corona Virus-2 Syndrome
title_full_unstemmed Extracellular Vesicle Associated miRNAs Regulate Signaling Pathways Involved in COVID-19 Pneumonia and the Progression to Severe Acute Respiratory Corona Virus-2 Syndrome
title_short Extracellular Vesicle Associated miRNAs Regulate Signaling Pathways Involved in COVID-19 Pneumonia and the Progression to Severe Acute Respiratory Corona Virus-2 Syndrome
title_sort extracellular vesicle associated mirnas regulate signaling pathways involved in covid-19 pneumonia and the progression to severe acute respiratory corona virus-2 syndrome
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8696174/
https://www.ncbi.nlm.nih.gov/pubmed/34956213
http://dx.doi.org/10.3389/fimmu.2021.784028
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