Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon

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.

Corticosteroid injections during the COVID-19 pandemic

“…Researchers have reported that the prevalence of asthma and COPD among hospitalised COVID-19 patients may be lower than in the general population 22 and recent research by Finney et al 23 has demonstrated using human and animal in vitro and in vivo disease models that inhaled corticosteroid (ICS) administration attenuates pulmonary expression of the SARS-CoV2 viral entry receptor angiotensin-converting enzyme (ACE)-2 which it is postulated may result in reduced susceptibility to COVID-19 infection. Systemic steroids may also mediate suppression of IFN and attenuate ACE2 expression.…”

COVID-19 and COPD: a narrative review of the basic science and clinical outcomes

“…The corticosteroid ciclesonide also appears to attenuate SARS-CoV-2 replication in vitro by targeting non-structural protein 15, an endoribonuclease which helps evade host detection of viral double-stranded RNA and type 1 IFN responses [ 89 – 91 ]. ICS may also prevent SARS-CoV-2 entry; ACE2 gene expression is lower in the sputum of COPD and asthma patients who use ICS compared to those who do not [ 92 , 93 ]. Furthermore, studies in mice have shown that ICS reduce ACE2 expression by inhibiting type 1 IFN production [ 92 ].…”

“…ICS may also prevent SARS-CoV-2 entry; ACE2 gene expression is lower in the sputum of COPD and asthma patients who use ICS compared to those who do not [ 92 , 93 ]. Furthermore, studies in mice have shown that ICS reduce ACE2 expression by inhibiting type 1 IFN production [ 92 ]. While suppression of type 1 IFN secretion may reduce host defence, the associated reduction of ACE2 expression may protect against SARS-CoV-2 cellular entry.…”

Zoonotic coronavirus epidemics

“…168 In vitro, a combination of glycopyrronium, formoterol, and budesonide appeared to inhibit viral replication in infected nasal and tracheal epithelial cells 169 and ACE2 expression was found to be decreased in sputum cells of asthmatic and COPD patients on ICS. 163,170 Questions have also been raised regarding the effect of type 2 biologic therapy on COVID-19 infectivity and outcomes. Observational experiences reported to date do not provide evidence that type 2 biologics are associated with increased risk for COVID-19 infection or higher COVID-19 disease severity.…”

“… 168 In vitro, a combination of glycopyrronium, formoterol, and budesonide appeared to inhibit viral replication in infected nasal and tracheal epithelial cells 169 and ACE2 expression was found to be decreased in sputum cells of asthmatic and COPD patients on ICS. 163 , 170 …”