期刊论文详细信息
Respiratory Research 卷:22
Dysregulation of COVID-19 related gene expression in the COPD lung
the MICA II Studygroup1  Fredrik Karlsson2  Karl Nordström2  Doriana Cellura3  Kris Ostridge3  Alastair Watson3  Tom Wilkinson3  Anna Freeman3  Hannah Burke3  C. Mirella Spalluto3  Karl J. Staples3  Damla Etal4  Graham Belfield4  Bastian Angermann5  Lisa Öberg5  Michael Hühn5  Daniel Muthas5 
[1] ;
[2] Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca;
[3] Faculty of Medicine, University of Southampton;
[4] Translational Genomics, Discovery Biology, Discovery Sciences, AstraZeneca;
[5] Translational Science and Experimental Medicine, Research and Early Development, AstraZeneca;
关键词: COPD;    ACE2;    COVID-19;    SARS-CoV-2;    Infection;    Inflammation;   
DOI  :  10.1186/s12931-021-01755-3
来源: DOAJ
【 摘 要 】

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.

【 授权许可】

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