Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background: The mechanisms underlying altered susceptibility and propensity to severe Coronavirus disease 2019 (COVID-19) disease in at-risk groups such as patients with chronic obstructive pulmonary disease (COPD) are poorly understood. Inhaled corticosteroids (ICS) are widely used in COPD but the extent to which these therapies protect or expose patients to risk of severe COVID-19 is unknown.
Objective: The aim of this study was to evaluate the effect of ICS upon pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme (ACE)-2.
Methods: We evaluated the effect of ICS administration upon pulmonary ACE2 expression in vitro in human airway epithelial cell cultures and in vivo in mouse models of ICS administration. Mice deficient in the type I interferon-α/β receptor (Ifnar1−/−) and exogenous interferon-β administration experiments were used to study the functional role of type-I IFN signalling in ACE2 expression. We compared sputum ACE2 expression in patients with COPD stratified according to use or non-use of ICS.
Results
ICS administration attenuated ACE2 expression in mice, an effect that was reversed by exogenous interferon-β administration and Ifnar1−/− mice had reduced ACE2 expression, indicating that type I interferon contributes mechanistically to this effect. ICS administration attenuated expression of ACE2 in COPD airway epithelial cell cultures and in mice with elastase-induced COPD-like changes. COPD patients taking ICS also had reduced sputum expression of ACE2 compared to non-ICS users.
Conclusion: ICS therapies in COPD reduce expression of the SARS-CoV-2 entry receptor ACE2. This effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD.
Objective: The aim of this study was to evaluate the effect of ICS upon pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme (ACE)-2.
Methods: We evaluated the effect of ICS administration upon pulmonary ACE2 expression in vitro in human airway epithelial cell cultures and in vivo in mouse models of ICS administration. Mice deficient in the type I interferon-α/β receptor (Ifnar1−/−) and exogenous interferon-β administration experiments were used to study the functional role of type-I IFN signalling in ACE2 expression. We compared sputum ACE2 expression in patients with COPD stratified according to use or non-use of ICS.
Results
ICS administration attenuated ACE2 expression in mice, an effect that was reversed by exogenous interferon-β administration and Ifnar1−/− mice had reduced ACE2 expression, indicating that type I interferon contributes mechanistically to this effect. ICS administration attenuated expression of ACE2 in COPD airway epithelial cell cultures and in mice with elastase-induced COPD-like changes. COPD patients taking ICS also had reduced sputum expression of ACE2 compared to non-ICS users.
Conclusion: ICS therapies in COPD reduce expression of the SARS-CoV-2 entry receptor ACE2. This effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD.
Date Issued
2021-02-01
Date Acceptance
2020-09-28
Citation
Journal of Allergy and Clinical Immunology, 2021, 147 (2), pp.510-519.e5
ISSN
0091-6749
Publisher
Elsevier
Start Page
510
End Page
519.e5
Journal / Book Title
Journal of Allergy and Clinical Immunology
Volume
147
Issue
2
Copyright Statement
© 2020 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Sponsor
Wellcome Trust
British Society for Antimicrobial Chemotherapy
Wellcome Trust
Medical Research Council (MRC)
Identifier
https://www.sciencedirect.com/science/article/pii/S009167492031407X?via%3Dihub
Grant Number
215275/Z/19/Z
BSAC-COVID-09
096382/Z/11/Z
MR/P028225/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Allergy
Immunology
COPD
COVID-19
inhaled corticosteroids
viral infection
PULMONARY-DISEASE
FLUTICASONE
PROPIONATE
EXPRESSION
IMMUNITY
MODEL
COPD
COVID-19
inhaled corticosteroids
viral infection
Administration, Inhalation
Adrenal Cortex Hormones
Aged
Angiotensin-Converting Enzyme 2
Animals
Bronchi
COVID-19
Cells, Cultured
Disease Susceptibility
Down-Regulation
Epithelial Cells
Female
Humans
Interferon Type I
Lung
Male
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Pulmonary Disease, Chronic Obstructive
Receptor, Interferon alpha-beta
SARS-CoV-2
Serine Endopeptidases
Lung
Bronchi
Cells, Cultured
Epithelial Cells
Animals
Mice, Inbred C57BL
Mice, Knockout
Humans
Pulmonary Disease, Chronic Obstructive
Disease Susceptibility
Adrenal Cortex Hormones
Serine Endopeptidases
Interferon Type I
Administration, Inhalation
Down-Regulation
Aged
Middle Aged
Female
Male
Receptor, Interferon alpha-beta
COVID-19
Angiotensin-Converting Enzyme 2
SARS-CoV-2
1107 Immunology
Allergy
Publication Status
Published
Date Publish Online
2020-10-15