Dysregulation of COVID-19 related gene expression in the COPD lung

Respiratory Research

Fredrik Karlsson¹  Karl Nordström¹  C. Mirella Spalluto²  Alastair Watson²  Karl J. Staples²  Tom Wilkinson²  Hannah Burke²  Doriana Cellura²  Anna Freeman²  Kris Ostridge³  Graham Belfield⁴  Damla Etal⁴  Daniel Muthas⁵  Bastian Angermann⁵  Michael Hühn⁵  Lisa Öberg⁵ 

[1] Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden;Faculty of Medicine, University of Southampton, Southampton, UK;NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK;Faculty of Medicine, University of Southampton, Southampton, UK;Translational Science and Experimental Medicine, Research and Early Development, AstraZeneca, Respiratory & Immunology, BioPharmaceuticals R&D, Gothenburg, Sweden;Clinical Development, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;Translational Genomics, Discovery Biology, Discovery Sciences, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, Sweden;Translational Science and Experimental Medicine, Research and Early Development, AstraZeneca, Respiratory & Immunology, BioPharmaceuticals R&D, Gothenburg, Sweden;

关键词: COPD;    ACE2;    COVID-19;    SARS-CoV-2;    Infection;    Inflammation;   

DOI  :  10.1186/s12931-021-01755-3

来源: Springer

【 摘 要 】

BackgroundChronic 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.MethodsWe quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects.ResultsACE2 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).ConclusionThis 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】

CC BY