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Dysregulation of COVID-19 related gene expression in the COPD lung

Dysregulation of COVID-19 related gene expression in the COPD lung
Dysregulation of COVID-19 related gene expression in the COPD lung
Background: chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from COVID-19. Early data suggest increased expression of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2), but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. To determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung and relationship to disease characteristics in COPD.

Methods: we quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects.

Results: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p=0.042) and biopsies (0.23, p=0.050), and correlated with worse lung function (r=-0.28, p=0.0090). Angiotensin converting enzyme 2 (ACE2) was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p=0.00045). Increased ACE2 expression also associated with use of ACE inhibitors (ACEi) (0.50, p=0.0034) and having cardiovascular disease (0.23, p=0.048) or hypertension (0.34, p=0.0089) and inhaled corticosteroid use in COPD subjects in biopsies (0.33, p=0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD biopsies compared to HV-ES controls with log2FC of –0.26 (p=0.033) and -0.40, (p=0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p=0.0051).

Conclusion: this analysis reveals the potential mechanisms driving susceptibility to SARS-CoV-2 infection and inflammation associated with severe COVID-19 seen in COPD. Extension of this approach to other viruses may lead to opportunities for therapeutic development to improve outcomes in the pandemic and beyond.
ACE2, COPD, COVID-19, Infection, Inflammation, SARS-CoV-2
1465-9921
Watson, Alastair
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Oberg, Lisa
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Angermann, Bastian
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Spalluto, C. Mirella
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Huhn, Michael
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Burke, Hannah
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Cellura, Doriana
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Freeman, Anna
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Muthas, Daniel
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Etal, Damla
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Belfield, Graham
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Karlsson, Fredrik
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Nordstrom, Karl
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Ostridge, Kristoffer
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Staples, Karl J.
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Wilkinson, Thomas
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Watson, Alastair
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Oberg, Lisa
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Angermann, Bastian
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Spalluto, C. Mirella
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Huhn, Michael
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Burke, Hannah
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Cellura, Doriana
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Freeman, Anna
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Muthas, Daniel
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Etal, Damla
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Belfield, Graham
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Karlsson, Fredrik
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Nordstrom, Karl
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Ostridge, Kristoffer
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Staples, Karl J.
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Wilkinson, Thomas
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Watson, Alastair, Oberg, Lisa, Angermann, Bastian, Spalluto, C. Mirella, Huhn, Michael, Burke, Hannah, Cellura, Doriana, Freeman, Anna, Muthas, Daniel, Etal, Damla, Belfield, Graham, Karlsson, Fredrik, Nordstrom, Karl, Ostridge, Kristoffer, Staples, Karl J. and Wilkinson, Thomas (2021) Dysregulation of COVID-19 related gene expression in the COPD lung. Respiratory Research, 22 (1), [164]. (doi:10.1186/s12931-021-01755-3).

Record type: Article

Abstract

Background: chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from COVID-19. Early data suggest increased expression of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2), but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. To determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung and relationship to disease characteristics in COPD.

Methods: we quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects.

Results: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p=0.042) and biopsies (0.23, p=0.050), and correlated with worse lung function (r=-0.28, p=0.0090). Angiotensin converting enzyme 2 (ACE2) was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p=0.00045). Increased ACE2 expression also associated with use of ACE inhibitors (ACEi) (0.50, p=0.0034) and having cardiovascular disease (0.23, p=0.048) or hypertension (0.34, p=0.0089) and inhaled corticosteroid use in COPD subjects in biopsies (0.33, p=0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD biopsies compared to HV-ES controls with log2FC of –0.26 (p=0.033) and -0.40, (p=0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p=0.0051).

Conclusion: this analysis reveals the potential mechanisms driving susceptibility to SARS-CoV-2 infection and inflammation associated with severe COVID-19 seen in COPD. Extension of this approach to other viruses may lead to opportunities for therapeutic development to improve outcomes in the pandemic and beyond.

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Accepted/In Press date: 17 May 2021
Published date: 29 May 2021
Keywords: ACE2, COPD, COVID-19, Infection, Inflammation, SARS-CoV-2

Identifiers

Local EPrints ID: 449333
URI: http://eprints.soton.ac.uk/id/eprint/449333
ISSN: 1465-9921
PURE UUID: 886f2270-894e-44c6-9026-ce622bf2d23c
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457

Catalogue record

Date deposited: 25 May 2021 16:32
Last modified: 26 Nov 2021 02:51

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Contributors

Author: Alastair Watson
Author: Lisa Oberg
Author: Bastian Angermann
Author: C. Mirella Spalluto
Author: Michael Huhn
Author: Hannah Burke
Author: Doriana Cellura
Author: Anna Freeman
Author: Daniel Muthas
Author: Damla Etal
Author: Graham Belfield
Author: Fredrik Karlsson
Author: Karl Nordstrom
Author: Kristoffer Ostridge
Author: Karl J. Staples ORCID iD

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