41: Rhinovirus-induced epithelial RIG-I inflammasome activation suppresses antiviral immunity and promotes inflammatory responses in virus-induced asthma exacerbations and COVID-19

Radzikowska, Urszula1,2,3; Eljaszewicz, Andrzej1,2,3; Tan, Ge1,4; Stocker, Nino1; Heider, Anja1; Westermann, Patrick1; Steiner, Silvio5,6,7; Dreher, Anita1,2; Wawrzyniak, Paulina1,2,8; Rückert, Beate1; Rodriguez-Coira, Juan1,9; Zhakparov, Damir1; Huang, Mengting1; Jakiela, Bogdan10; Sanak, Marek10; Moniuszko, Marcin3,11; O`Mahony, Liam1,12; Kebadze, Tatiana13; Jackson, David14; Edwards, Michael15; Thiel, Volker5; Johnston, Sebastian16; Akdis Cezmi1,2,&; Sokolowska, Milena1,2,&

  1. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
  2. Christine Kühne – Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
  3. Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland
  4. Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland
  5. Institute of Virology and Immunology (IVI), Bern, Switzerland
  6. Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
  7. Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
  8. Division of Clinical Chemistry and Biochemistry, University Children`s Hospital Zurich and Children`s Research Center, University Children`s Hospital Zurich, Zurich, Switzerland
  9. IMMA, Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities Madrid, Spain; Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities Madrid, Spain
  10. Department of Internal Medicine, Jagiellonian University Medical College, Cracow, Poland
  11. Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
  12. Department of Medicine and School of Microbiology, APC Microbiome Ireland, University College Cork, Ireland
  13. National Heart and Lung Institute Imperial College London, United Kingdom; Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom
  14. Guy’s Severe Asthma Centre, School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom
  15. Guy's & St Thomas' NHS Trust SE1 9RT; GSTT & South Thames Asthma Network Guy's Severe Asthma Centre, Guy's Hospital; Faculty of Life Sciences & Medicine King's College London, London, United Kingdom
  16. National Heart and Lung Institute Imperial College, London, United Kingdom; Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Imperial College Healthcare NHS Trust, London, United Kingdom

& Senior Co-Authorship

Rhinoviruses (RV) and inhaled allergens, such as house dust mite (HDM) are the major agents responsible for life-threatening asthma exacerbations. The mechanisms of this virus-allergen interactions in airway epithelium in asthma are largely unknown. To address this, we compared molecular mechanisms of HDM and RV interactions in experimental RV infection in patients with asthma and healthy individuals. RV infection was sensed via retinoic acid-inducible gene I (RIG-I) helicase, but not via NLR family pyrin domain containing 3 (NLRP3), which led to subsequent apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) recruitment, oligomerization and RIG-I inflammasome activation.

This phenomenon was augmented in bronchial epithelium in patients with asthma, especially upon pre-exposure to HDM, which itself induced pro-IL-1b release and early inhibition of RIG-I/TANK binding kinase 1/IkB kinase e /type I/III interferons (RIG-I/TBK1/IKKe/IFN-I/III) responses. Excessive activation of RIG-I inflammasomes was partially responsible for alteration and persistence of type I/III IFN responses, prolonged viral clearance and unresolved inflammation in asthma. Finally, we investigated the role of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in exacerbations of asthma or the influence of preexisting viral or allergic airway inflammation on the development of coronavirus disease 2019 (COVID-19).

We found, that RV/HDM-induced sustained IFN I/III responses initially restricted SARS-CoV-2 replication in epithelium of patients with asthma, but even this limited infection with SARS-CoV-2 augmented RIG-I inflammasome activation. In summary, timely inhibition of the epithelial IL-1b signaling may lead to more efficient viral clearance and lower the burden of RV and SARS-CoV-2 infection.