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How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning<jats:italic>ISG<\/jats:italic>induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To decipher the functions of gasdermin B (encoded by<jats:italic>GSDMB<\/jats:italic>) in respiratory virus-induced lung inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In two independent cohorts, we analysed expression correlation between<jats:italic>GSDMB<\/jats:italic>and<jats:italic>ISG<\/jats:italic><jats:italic>s<\/jats:italic>. In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated<jats:italic>GSDMB<\/jats:italic>-overexpressing and<jats:italic>GSDMB<\/jats:italic>-deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of<jats:italic>GSDMB<\/jats:italic>for<jats:italic>ISG<\/jats:italic>induction. We also generated a novel transgenic mouse line with inducible expression of human unique<jats:italic>GSDMB<\/jats:italic>gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of<jats:italic>GSDMB<\/jats:italic>in respiratory syncytial virus-induced lung inflammation<jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>GSDMB<\/jats:italic>is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium,<jats:italic>GSDMB<\/jats:italic>is induced by respiratory viral infections. Expression of<jats:italic>GSDMB<\/jats:italic>and<jats:italic>ISGs<\/jats:italic>significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human<jats:italic>GSDMB<\/jats:italic>in mouse airway epithelium led to enhanced<jats:italic>ISGs<\/jats:italic>induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>GSDMB<\/jats:italic>promotes<jats:italic>ISGs<\/jats:italic>expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.01232-2023","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T16:45:17Z","timestamp":1711039517000},"page":"2301232","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway 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