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Authors:Finney et al 

Journal/ Pre-Print:bioRxiv 

Tags: Cell Biology, Clinical, Drug discovery/Drug repurpose, Inflammation, Molecular biology, Therapeutics 

Research Highlights

  • Inhaled corticosteroid (ICS) decrease ACE2 expression in COPD patients, in vitro, and in mouse models of COPD 

  • Effect of ICS is by decreasing type I interferon, which leads to a decrease in ACE2  

Summary

This work from Finney et al uses a COPD patient cohort, in vitro, and in vivo mouse models to explore the relationship between inhaled corticosteroids and ACE2 expression. Because COPD patients appear to have worse outcomes in COVID-19 but do not seem to be infected at a rate as high as the general population, the authors propose that ICS use may be the link between these two phenomena. They convincingly show that ACE2 is decreased upon ICS use, and this is likely through their effect on the interferon pathway. Sputum ACE2 mRNA is greater in COPD patients who do not use ICS but does not affect TMPRSS2 expression. Ex vivo cultured bronchial epithelial cells of COPD patients expresses more ACE2 mRNA than healthy controls, which is reversed with fluticasone. In C57BL6 mice, intranasal corticosteroids decrease ACE2 RNA and protein expression in lung tissue. This can be reversed with administration of recombinant IFN-β. The authors suggest a relationship between IFN signalling and Ace2 expression; in vivo, there is a positive correlation between Ace2 mRNA expression 2’-5’OAS mRNA and BAL IFN-λ protein. Furthermore, Ifnar1-/- mice have reduced pulmonary Ace2 mRNA. It will be interesting to understand how these data relate to the recent study showing dexamethasone improves survival in the most severe COVID-19 cases. 

Impact for SARS-CoV2/COVID19 research efforts  

Understand the virology and/or cell biology of SARS-CoV2/COVID19 

ICS decrease ACE2 expression and therefore may affect viral entry into airway epithelial cells in COPD patients. 
 

Study Type 

  • In vitro study 

  • In vivo study (mouse) 

  • Clinical Cohort study 

Strengths and limitations of the paper 

Novelty: This paper demonstrates that COPD patients on ICS have lower ACE2 expression than other COPD patients. Mouse and in vitro data strengthens the connection between interferon and ACE2. 

Standing in the field: The connection between ACE2 and interferon has been established.  This paper connects the published data with a cohort of COPD patients and strengthens the evidence in the field that interferon regulates its expression. Previous studies suggest a low frequency of cases with chronic lung diseases but increased risk of adverse outcome. The authors suggest that prior ICS treatment may prevent viral acquisition due to the reduced ACE2 expression. However, upon infection there is a higher risk of adverse outcome as ACE2 is protective against lung injury. ICS may in fact be protective for COVID 19 severe cases, although this study still needs to directly test this with the virus.  

Recent results from a large randomised clinical trial shows that corticosteroid treatment is also therapeutic in severe cases. The RECOVERY clinical trial which found that the corticosteroid dexamethasone prevents 1 out of 8 deaths for severe cases on ventilators. Interestingly there is no effect of the drug on cases not requiring respirators. 

Appropriate statistics:Stats are fine. They give p values when differences are not significant. 

Viral model used:No viral model was used 

Translatability:This study could impact the understanding of how COPD patients progress with COVID19, but without viral infection data, the translatability is limited. 

Main limitations: The paper does not include viral infection data to support the hypothesis that lower ACE2 expression driven by lower IFN during ICS treatment would affect infectivity of SARS-CoV2.