Authors: Tao Liu, Siqi Liu, Xianliang Rui, Ye Cao, Julian Hecker, Feng Guo, Yihan Zhang, Lu Gong, Yihan Zhou, Yuzhen Yu, Nandini Krishnamoorthyni, Samuel Bates, Sung Chun, Nathan Boyer, Shuang Xu, Jin-Ah Park, Mark A. Perrella, Bruce D. Levy, Scott T. Weiss, Hongmei Mou, Benjamin A. Raby, Xiaobo Zhou
Published: 2024-03-21
DOI: 10.1183/13993003.01232-2023
Source: Full article
RationaleRespiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes (ISGs). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuningISGinduction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown.ObjectivesTo decipher the functions of gasdermin B (encoded byGSDMB) in respiratory virus-induced lung inflammation.MethodsIn two independent cohorts, we analysed expression correlation betweenGSDMBandISGs. In human bronchial epithelial cell line or primary bronchial epithelial cells, we generatedGSDMB-overexpressing andGSDMB-deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism ofGSDMBforISGinduction. We also generated a novel transgenic mouse line with inducible expression of human uniqueGSDMBgene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role ofGSDMBin respiratory syncytial virus-induced lung inflammationin vivo.ResultsGSDMBis 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,GSDMBis induced by respiratory viral infections. Expression ofGSDMBandISGssignificantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of humanGSDMBin mouse airway epithelium led to enhancedISGsinduction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection.ConclusionsGSDMBpromotesISGsexpression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.