Lisa Öberg1, Bastian Angermann1, Alastair Watson2,3, C Mirella Spalluto2,3, Michael Hühn1, Hannah Burke2,3, Doriana Cellura2,3, Anna Freeman2,3, Daniel Muthas1, Damla Etal4, Graham Belfield4, Fredrik Karlsson5, Karl Nordström5, Kris Ostridge2,1,6, Karl J Staples2,3, Tom Wilkinson7,8. 1. Translational Science and Experimental Medicine, Research and Early Development, AstraZeneca, Respiratory & Immunology, BioPharmaceuticals R&D, Gothenburg, Sweden. 2. Faculty of Medicine, University of Southampton, Southampton, UK. 3. NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK. 4. Translational Genomics, Discovery Biology, Discovery Sciences, AstraZeneca, BioPharmaceuticals R&D, Gothenburg, Sweden. 5. Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. 6. Clinical Development, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 7. Faculty of Medicine, University of Southampton, Southampton, UK. t.wilkinson@soton.ac.uk. 8. NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK. t.wilkinson@soton.ac.uk.
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.
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 ACEinhibitors (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.
Authors: Kristoffer Ostridge; Nicholas Williams; Viktoriya Kim; Michael Bennett; Stephen Harden; Lindsay Welch; Simon Bourne; Ngaire A Coombs; Paul T Elkington; Karl J Staples; Tom M A Wilkinson Journal: Thorax Date: 2015-12-08 Impact factor: 9.139
Authors: Annemarie B Docherty; Ewen M Harrison; Christopher A Green; Hayley E Hardwick; Riinu Pius; Lisa Norman; Karl A Holden; Jonathan M Read; Frank Dondelinger; Gail Carson; Laura Merson; James Lee; Daniel Plotkin; Louise Sigfrid; Sophie Halpin; Clare Jackson; Carrol Gamble; Peter W Horby; Jonathan S Nguyen-Van-Tam; Antonia Ho; Clark D Russell; Jake Dunning; Peter Jm Openshaw; J Kenneth Baillie; Malcolm G Semple Journal: BMJ Date: 2020-05-22
Authors: Sergey N Avdeev; Andrey I Yaroshetskiy; Natalia A Tsareva; Zamira M Merzhoeva; Natalia V Trushenko; Galina V Nekludova; Svetlana Yu Chikina Journal: Am J Emerg Med Date: 2020-10-01 Impact factor: 2.469
Authors: Ludovico Cantuti-Castelvetri; Ravi Ojha; Liliana D Pedro; Minou Djannatian; Jonas Franz; Suvi Kuivanen; Franziska van der Meer; Katri Kallio; Tuğberk Kaya; Maria Anastasina; Teemu Smura; Lev Levanov; Leonora Szirovicza; Allan Tobi; Hannimari Kallio-Kokko; Pamela Österlund; Merja Joensuu; Frédéric A Meunier; Sarah J Butcher; Martin Sebastian Winkler; Brit Mollenhauer; Ari Helenius; Ozgun Gokce; Tambet Teesalu; Jussi Hepojoki; Olli Vapalahti; Christine Stadelmann; Giuseppe Balistreri; Mikael Simons Journal: Science Date: 2020-10-20 Impact factor: 47.728
Authors: Hannah Burke; Anna Freeman; Paul O'Regan; Oskar Wysocki; Andre Freitas; Ahilanandan Dushianthan; Michael Celinski; James Batchelor; Hang Phan; Florina Borca; Natasha Sheard; Sarah Williams; Alastair Watson; Paul Fitzpatrick; Dónal Landers; Tom Wilkinson Journal: BMJ Open Date: 2022-02-15 Impact factor: 2.692
Authors: Laura V Reid; C Mirella Spalluto; Alastair Watson; Karl J Staples; Tom M A Wilkinson Journal: Front Immunol Date: 2021-12-02 Impact factor: 7.561
Authors: Ioannis Kyrou; Emmanouil Karteris; Rachel Kerslake; Harpal S Randeva; Danny Jonigk; Christopher Werlein; Jan L Robertus; Periklis Katopodis; Petra Jasker; Demetrios A Spandidos Journal: Mol Med Rep Date: 2022-02-25 Impact factor: 2.952
Authors: Horst Olschewski; Ernst Eber; Brigitte Bucher; Klaus Hackner; Sabin Handzhiev; Konrad Hoetzenecker; Marco Idzko; Walter Klepetko; Gabor Kovacs; Bernd Lamprecht; Judith Löffler-Ragg; Michael Meilinger; Alexander Müller; Christian Prior; Otmar Schindler; Helmut Täubl; Angela Zacharasiewicz; Ralf Harun Zwick; Britt-Madelaine Arns; Josef Bolitschek; Katharina Cima; Elisabeth Gingrich; Maximilian Hochmair; Fritz Horak; Peter Jaksch; Roland Kropfmüller; Andreas Pfleger; Bernhard Puchner; Christoph Puelacher; Patricia Rodriguez; Helmut J F Salzer; Peter Schenk; Ingrid Stelzmüller; Volker Strenger; Matthias Urban; Marlies Wagner; Franz Wimberger; Holger Flick Journal: Wien Klin Wochenschr Date: 2022-04-21 Impact factor: 2.275