Tao Liu, PhD
Channing Division of Network Medicine
Tao Liu*, Siqi Liu, Xianliang Rui, Feng Guo, Yihan Zhang, Lu Gong, Julian Hecker, 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
Rationale: Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, often due to over-activated interferon response. How viral infection-induced interferon response subsequently leads to exuberant airway inflammation in genetically susceptible asthmatics remains largely unknown.
Methods: In primary human bronchial epithelial cells or human bronchial epithelial cell line, we generated GSDMB-overexpressing and -deficient cells. By performing qpcr, Elisa and co-immunoprecipitation (co-IP), we assessed the target of GSDMB to interferon response. In two independent cohorts, we analyzed the correlation between GSDMB and interferon response. Also, we generated a mice model with inducible expression of human unique GSDMB gene in mouse airway epithelial cells and established a repetitive RSV infection model in the neonatal stage to detect the role of GSDMB on RSV-induced inflammation.
Results: We demonstrate that gasdermin B encoded by GSDMB, one of the most significant asthma-susceptible genes at 17q21, acts as a novel RNA sensor, promoting MAVS-TBK1 signaling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and interferon-stimulated genes significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible and conditional expression of human GSDMB gene in mouse airway epithelium leads to the enhanced interferon response, increased airway inflammation with mucus hyper-secretion upon neonatal respiratory syncytial virus infection.
Conclusion: GSDMB, a novel RNA sensor, promotes interferon response and enhances airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.
This research has clinical implications for understanding the mechanisms behind asthma exacerbation caused by respiratory viral infections. The study demonstrates that gasdermin B, which is encoded by the asthma-susceptible gene GSDMB at 17q21, acts as a novel RNA sensor, promoting inflammation in response to respiratory viral infections. The expression of GSDMB and interferon-stimulated genes significantly correlated in respiratory epithelium from two independent asthma cohorts. The study also shows that inducible and conditional expression of human GSDMB gene in mouse airway epithelium leads to enhanced interferon response, increased airway inflammation, and mucus hyper-secretion upon neonatal respiratory syncytial virus infection. These findings suggest that targeting GSDMB and interferon response could be a potential therapeutic strategy for preventing asthma exacerbation caused by respiratory viral infections.