Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation.

RATIONALE

Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes (). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown.

OBJECTIVES

To decipher the functions of gasdermin B (encoded by ) in respiratory virus-induced lung inflammation.

METHODS

In two independent cohorts, we analysed expression correlation between and . In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated -overexpressing and -deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of for induction. We also generated a novel transgenic mouse line with inducible expression of human unique gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of in respiratory syncytial virus-induced lung inflammation .

RESULTS

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, is induced by respiratory viral infections. Expression of and significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human in mouse airway epithelium led to enhanced induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection.

CONCLUSIONS

promotes expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.