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

Abstract

Rhinoviruses (RV) and inhaled allergens, such as house dust mite (HDM) are the major agents responsible for asthma onset, its life-threatening exacerbations and progression to severe disease. 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) is largely unknown. To address this, we compared molecular mechanisms of HDM, RV and SARS-CoV-2 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 a priming step, pro-IL-1β release and early inhibition of RIG-I/TANK binding kinase 1/IκB kinase ε /type I/III interferons (RIG-I/TBK1/IKKε/IFN-I/III) responses. Excessive activation of RIG-I inflammasomes was partially responsible for the alteration and persistence of type I/III IFN responses, prolonged viral clearance and unresolved inflammation in asthma. 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. Timely inhibition of the epithelial RIG-I inflammasome and reduction of IL-1β signaling may lead to more efficient viral clearance and lower the burden of RV and SARS- CoV-2 infection.

Transcriptomics of rhinovirus persistence reveals sustained expression of RIG‐I and interferon‐stimulated genes in nasal epithelial cells in vitro

“…dpi. 59 This may be attributed to the different temporal dynamics of infection (i.e., time-points), different models used (i.e., in vitro and in vivo), and viral clearance by immune cells. Therefore, it is crucial to also investigate the role of peripheral blood mononuclear cells (PBMCs) in viral clearance and the cross-talk with antiviral-signaling in infected hNECs or hBECs of healthy control and asthmatic subjects.…”

Regulation of mRNA transcripts, protein isoforms, glycosylation and spatial localization of ACE2 and other SARS-CoV-2-associated molecules in human airway epithelium upon viral infection and type 2 inflammation

“…SARS-CoV-2 RNA is recognized by MDA5 47 . Infection with RV initiates type I/III IFN response, therefore pre-infection with rhinovirus reduces SARS-CoV-2 replication 48 , but RV and SARS-CoV-2 co-infection leads to the greater damage of airway epithelium, especially in patients with asthma 21 . An observed ACE2 increase was caused presumably by an increase in short ACE2 mRNA, as we demonstrated above.…”

“…Moreover, infection with rhinovirus (RV), the most common exacerbation-inducing factor in asthma, has been shown to inhibit SARS-CoV-2 infection via type I/III IFN-dependent mechanism [18][19][20] , which might suggest that this mechanism could constitute some form of protection. However, we recently reported that co-infection of rhinovirus (RV) and SARS-CoV-2 leads to a greater retinoic acid-inducible gene I (RIG-I) inflammasome-dependent damage of airway epithelium in patients with asthma 21 , which is strongly supported by the clinical findings that patients with RV and SARS-CoV-2 coinfection are more prone to severe COVID-19 22 . Finally, some components of house dust mite (HDM) or birch pollen allergens were demonstrated to decrease type I/III IFN responses 21,23 at the mucosal sites, a mechanism which may potentially contribute to the reported correlations between high allergen exposure and increased SARS-CoV-2 infection rates 24 .…”

EV-A71 induced IL-1β production in THP-1 macrophages is dependent on NLRP3, RIG-I, and TLR3

“…The RIG-I inflammasome is activated in primary lung epithelial cells and peripheral blood mononuclear cells. Furthermore, the activation of the epithelial RIG-I inflammasome is implicated in virus-induced inflammatory responses 47 .…”