Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon
Lydia J Finney1, Nicholas Glanville2, Hugo Farne1
1National Heart and Lung Institute, Imperial College London, London, United Kingdom.
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 (ICSs) 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 ICSs following pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme-2 (ACE2).
Methods:
We evaluated the effect of ICS administration on 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 IFN-α/β receptor (Ifnar1-/-) and administration of exogenous IFN-β were used to study the functional role of type-I interferon signaling in ACE2 expression. We compared sputum ACE2 expression in patients with COPD stratified according to use or nonuse of ICS.
Results:
ICS administration attenuated ACE2 expression in mice, an effect that was reversed by exogenous IFN-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 airway epithelial cell cultures from patients with COPD and in mice with elastase-induced COPD-like changes. Compared with ICS nonusers, patients with COPD who were taking ICSs also had reduced sputum expression of ACE2.
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.
Insights
Inhaled corticosteroids (ICSs) reduce the expression of angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 entry receptor, in patients with chronic obstructive pulmonary disease (COPD). This finding suggests a potential mechanism for altered COVID-19 susceptibility in COPD patients using ICSs.
Area of Science:
- Pulmonary Medicine
- Virology
- Immunology
Background:
- Mechanisms of severe COVID-19 in chronic obstructive pulmonary disease (COPD) patients remain unclear.
- The role of inhaled corticosteroids (ICSs) in modulating COVID-19 risk for COPD patients is unknown.
Purpose of the Study:
- To investigate the impact of ICSs on the pulmonary expression of angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 viral entry receptor.
Main Methods:
- Evaluated ICS effects on ACE2 expression in human airway epithelial cells and mouse models.
- Utilized type I interferon receptor-deficient mice and exogenous interferon-beta to explore the role of type I interferon signaling.
- Compared sputum ACE2 expression in COPD patients with and without ICS use.
Main Results:
- ICS administration decreased ACE2 expression in both in vitro and in vivo models.
- Type I interferon signaling was mechanistically linked to ICS-mediated ACE2 reduction.
- COPD patients on ICSs exhibited lower sputum ACE2 expression compared to non-users.
Conclusions:
- ICS therapies for COPD demonstrably reduce the expression of ACE2.
- This reduction in the SARS-CoV-2 entry receptor may influence COVID-19 susceptibility in COPD patients.
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