Nazanin Zounemat Kermani1,2, Woo-Jung Song2,3, Yusef Badi1,2, Ali Versi1,2, Yike Guo1, Kai Sun1, Pank Bhavsar2, Peter Howarth4,5, Sven-Erik Dahlen6, Peter J Sterk7, Ratko Djukanovic4,5, Ian M Adcock1,2, Kian Fan Chung8,9. 1. Data Science Institute, Imperial College London, London, UK. 2. National Heart and Lung Institute, Imperial College London, Dovehouse St, London, SW3 6LY, UK. 3. Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. 4. Faculty of Medicine, Southampton University, Southampton, UK. 5. NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK. 6. Centre for Allergy Research, Karolinska Institute, Stockholm, Sweden. 7. Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands. 8. Data Science Institute, Imperial College London, London, UK. f.chung@imperial.ac.uk. 9. National Heart and Lung Institute, Imperial College London, Dovehouse St, London, SW3 6LY, UK. f.chung@imperial.ac.uk.
Abstract
BACKGROUND: Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells. METHODS: We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels. RESULTS: ACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes. CONCLUSION: Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.
BACKGROUND:Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells. METHODS: We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels. RESULTS:ACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes. CONCLUSION: Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.
Entities:
Keywords:
ACE2; FURIN; Neutrophil; Severe asthma; TMPRSS2
Authors: Michael C Peters; Satria Sajuthi; Peter Deford; Stephanie Christenson; Cydney L Rios; Michael T Montgomery; Prescott G Woodruff; David T Mauger; Serpil C Erzurum; Mats W Johansson; Loren C Denlinger; Nizar N Jarjour; Mario Castro; Annette T Hastie; Wendy Moore; Victor E Ortega; Eugene R Bleecker; Sally E Wenzel; Elliot Israel; Bruce D Levy; Max A Seibold; John V Fahy Journal: Am J Respir Crit Care Med Date: 2020-07-01 Impact factor: 21.405
Authors: Haijun Zhang; Mahboubeh R Rostami; Philip L Leopold; Jason G Mezey; Sarah L O'Beirne; Yael Strulovici-Barel; Ronald G Crystal Journal: Am J Respir Crit Care Med Date: 2020-07-15 Impact factor: 21.405
Authors: Joan C Smith; Erin L Sausville; Vishruth Girish; Monet Lou Yuan; Anand Vasudevan; Kristen M John; Jason M Sheltzer Journal: Dev Cell Date: 2020-05-16 Impact factor: 12.270
Authors: Carly G K Ziegler; Samuel J Allon; Sarah K Nyquist; Ian M Mbano; Vincent N Miao; Constantine N Tzouanas; Yuming Cao; Ashraf S Yousif; Julia Bals; Blake M Hauser; Jared Feldman; Christoph Muus; Marc H Wadsworth; Samuel W Kazer; Travis K Hughes; Benjamin Doran; G James Gatter; Marko Vukovic; Faith Taliaferro; Benjamin E Mead; Zhiru Guo; Jennifer P Wang; Delphine Gras; Magali Plaisant; Meshal Ansari; Ilias Angelidis; Heiko Adler; Jennifer M S Sucre; Chase J Taylor; Brian Lin; Avinash Waghray; Vanessa Mitsialis; Daniel F Dwyer; Kathleen M Buchheit; Joshua A Boyce; Nora A Barrett; Tanya M Laidlaw; Shaina L Carroll; Lucrezia Colonna; Victor Tkachev; Christopher W Peterson; Alison Yu; Hengqi Betty Zheng; Hannah P Gideon; Caylin G Winchell; Philana Ling Lin; Colin D Bingle; Scott B Snapper; Jonathan A Kropski; Fabian J Theis; Herbert B Schiller; Laure-Emmanuelle Zaragosi; Pascal Barbry; Alasdair Leslie; Hans-Peter Kiem; JoAnne L Flynn; Sarah M Fortune; Bonnie Berger; Robert W Finberg; Leslie S Kean; Manuel Garber; Aaron G Schmidt; Daniel Lingwood; Alex K Shalek; Jose Ordovas-Montanes Journal: Cell Date: 2020-04-27 Impact factor: 41.582
Authors: Flavio Protasio Veras; Marjorie Cornejo Pontelli; Camila Meirelles Silva; Juliana E Toller-Kawahisa; Mikhael de Lima; Daniele Carvalho Nascimento; Ayda Henriques Schneider; Diego Caetité; Lucas Alves Tavares; Isadora M Paiva; Roberta Rosales; David Colón; Ronaldo Martins; Italo Araujo Castro; Glaucia M Almeida; Maria Isabel Fernandes Lopes; Maíra Nilson Benatti; Letícia Pastorelli Bonjorno; Marcela Cavichioli Giannini; Rodrigo Luppino-Assad; Sérgio Luna Almeida; Fernando Vilar; Rodrigo Santana; Valdes R Bollela; Maria Auxiliadora-Martins; Marcos Borges; Carlos Henrique Miranda; Antônio Pazin-Filho; Luis Lamberti P da Silva; Larissa Dias Cunha; Dario S Zamboni; Felipe Dal-Pizzol; Luiz O Leiria; Li Siyuan; Sabrina Batah; Alexandre Fabro; Thais Mauad; Marisa Dolhnikoff; Amaro Duarte-Neto; Paulo Saldiva; Thiago Mattar Cunha; José Carlos Alves-Filho; Eurico Arruda; Paulo Louzada-Junior; Renê Donizeti Oliveira; Fernando Queiroz Cunha Journal: J Exp Med Date: 2020-12-07 Impact factor: 14.307
Authors: Jesse Fajnzylber; James Regan; Kendyll Coxen; Heather Corry; Colline Wong; Alexandra Rosenthal; Daniel Worrall; Francoise Giguel; Alicja Piechocka-Trocha; Caroline Atyeo; Stephanie Fischinger; Andrew Chan; Keith T Flaherty; Kathryn Hall; Michael Dougan; Edward T Ryan; Elizabeth Gillespie; Rida Chishti; Yijia Li; Nikolaus Jilg; Dusan Hanidziar; Rebecca M Baron; Lindsey Baden; Athe M Tsibris; Katrina A Armstrong; Daniel R Kuritzkes; Galit Alter; Bruce D Walker; Xu Yu; Jonathan Z Li Journal: Nat Commun Date: 2020-10-30 Impact factor: 14.919
Authors: Elisabet Pujadas; Fayzan Chaudhry; Russell McBride; Felix Richter; Shan Zhao; Ania Wajnberg; Girish Nadkarni; Benjamin S Glicksberg; Jane Houldsworth; Carlos Cordon-Cardo Journal: Lancet Respir Med Date: 2020-08-06 Impact factor: 30.700
Authors: Nazanin Zounemat Kermani; Woo-Jung Song; Yusef Badi; Ali Versi; Yike Guo; Kai Sun; Pank Bhavsar; Peter Howarth; Sven-Erik Dahlen; Peter J Sterk; Ratko Djukanovic; Ian M Adcock; Kian Fan Chung Journal: Respir Res Date: 2021-02-08
Authors: Linh T Bui; Nichelle I Winters; Mei-I Chung; Chitra Joseph; Austin J Gutierrez; Arun C Habermann; Taylor S Adams; Jonas C Schupp; Sergio Poli; Lance M Peter; Chase J Taylor; Jessica B Blackburn; Bradley W Richmond; Andrew G Nicholson; Doris Rassl; William A Wallace; Ivan O Rosas; R Gisli Jenkins; Naftali Kaminski; Jonathan A Kropski; Nicholas E Banovich Journal: Nat Commun Date: 2021-07-14 Impact factor: 14.919