tetano
Editor, Senior Moderator
Respir Res
. 2021 May 29;22(1):164.
doi: 10.1186/s12931-021-01755-3.
Dysregulation of COVID-19 related gene expression in the COPD lung
Alastair Watson[SUP] 1 2 [/SUP], Lisa Öberg[SUP] #[/SUP][SUP] 3 [/SUP], Bastian Angermann[SUP] #[/SUP][SUP] 3 [/SUP], C Mirella Spalluto[SUP] 1 2 [/SUP], Michael Hühn[SUP] 3 [/SUP], Hannah Burke[SUP] 1 2 [/SUP], Doriana Cellura[SUP] 1 2 [/SUP], Anna Freeman[SUP] 1 2 [/SUP], Daniel Muthas[SUP] 3 [/SUP], Damla Etal[SUP] 4 [/SUP], Graham Belfield[SUP] 4 [/SUP], Fredrik Karlsson[SUP] 5 [/SUP], Karl Nordström[SUP] 5 [/SUP], Kris Ostridge[SUP] 1 3 6 [/SUP], Karl J Staples[SUP] 1 2 [/SUP], Tom Wilkinson[SUP] 7 8 [/SUP], MICA II Studygroup
Collaborators, Affiliations
Abstract
Background: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection.
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 bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial 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). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively).
Conclusion: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.
Keywords: ACE2; COPD; COVID-19; Infection; Inflammation; SARS-CoV-2.
. 2021 May 29;22(1):164.
doi: 10.1186/s12931-021-01755-3.
Dysregulation of COVID-19 related gene expression in the COPD lung
Alastair Watson[SUP] 1 2 [/SUP], Lisa Öberg[SUP] #[/SUP][SUP] 3 [/SUP], Bastian Angermann[SUP] #[/SUP][SUP] 3 [/SUP], C Mirella Spalluto[SUP] 1 2 [/SUP], Michael Hühn[SUP] 3 [/SUP], Hannah Burke[SUP] 1 2 [/SUP], Doriana Cellura[SUP] 1 2 [/SUP], Anna Freeman[SUP] 1 2 [/SUP], Daniel Muthas[SUP] 3 [/SUP], Damla Etal[SUP] 4 [/SUP], Graham Belfield[SUP] 4 [/SUP], Fredrik Karlsson[SUP] 5 [/SUP], Karl Nordström[SUP] 5 [/SUP], Kris Ostridge[SUP] 1 3 6 [/SUP], Karl J Staples[SUP] 1 2 [/SUP], Tom Wilkinson[SUP] 7 8 [/SUP], MICA II Studygroup
Collaborators, Affiliations
- PMID: 34051791
- PMCID: PMC8164067
- DOI: 10.1186/s12931-021-01755-3
Abstract
Background: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection.
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 bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial 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). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively).
Conclusion: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.
Keywords: ACE2; COPD; COVID-19; Infection; Inflammation; SARS-CoV-2.