20th March, 2023 - 14:00 CET

Novel mechanisms controlling viral and allergic inflammation in airway epithelium

with

PD Dr. Milena Sokolowska

Specialist in Internal Medicine, Head Immune Metabolism
Swiss Institute of Allergy and Asthma Research (SIAF)
University of Zurich

Online Seminar via Zoom
Link and password upon request
Please write an e-mail to: iem-seminar.umweltmedizin@tum.de

Abstract:
Rhinoviruses (RV) and inhaled allergens, such as house dust mite (HDM) are the major agents responsible for asthma
onset, exacerbations and progression to the severe disease, but the mechanisms of these pathogenic reciprocal virusallergen
interactions are not well understood. To address this, we analyzed mechanisms of airway epithelial sensing
and response to RV infection using controlled experimental in vivo RV infection in healthy controls and patients with
asthma and in vitro models of HDM exposure and RV infection in primary airway epithelial cells. We found that
intranasal RV infection in patients with asthma led to the highly augmented inflammasome-mediated lower airway
inflammation detected in bronchial brushes, biopsies and bronchoalveolar lavage fluid. Mechanistically, RV infection
in bronchial airway epithelium led to retinoic acid-inducible gene I (RIG-I), but not via NLR family pyrin domain
containing 3 (NLRP3) inflammasome activation, which was highly augmented in patients with asthma, especially upon
pre-exposure to HDM. This excessive activation of RIG-I inflammasomes was responsible for the impairment of antiviral
type I/III interferons (IFN), prolonged viral clearance and unresolved inflammation in asthma in vivo and in vitro. Preexposure
to HDM amplifies RV-induced epithelial injury in patients with asthma via enhancement of pro-IL1
expression and release, additional inhibition of type I/III IFNs and activation of auxiliary proinflammatory and proremodeling
proteins. Finally, in order to determine whether RV-induced activation of RIG-I inflammasome may play a
role in the susceptibility to severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection in asthma, we
analyzed the effects of HDM exposure and RV/SARS-CoV-2 coinfection. We found that prior infection with RV tended
to restrict SARS-CoV-2 replication, but co-infection augmented RIG-I inflammasome activation and epithelial
inflammation in patients with asthma, especially in the presence of HDM. Timely inhibition of epithelial RIG-I
inflammasome activation may lead to more efficient viral clearance and lower the burden of RV and SARS-CoV-2
infections.