Project Summary Respiratory virus infection, an increasing health and social burden alone, also increases risk for development and exacerbation of other respiratory diseases, including asthma that affects 17 million U.S. people. Viral infection triggers innate immune response, an important defensive mechanism through activation of the interferon signaling: robust induction of antiviral proteins including interferons (IFNs) and interferon-stimulated genes (ISGs) through the recognition of viral nucleic acid and activation of subsequent signal cascades. Specifically, intracellular viral RNA is sensed and recognized by RNA sensors, which subsequently activates series of signaling cascade to induce the production of IFNs. Secreted IFNs, in turn, activates the transcription of hundreds of ISGs to amplify innate immune response, a double-edged sword, both constraining viral replication and without proper control, leading to exuberant inflammatory response that damages airway epithelium during asthma exacerbation caused by viral infection. Furthermore, such virus-induced asthmatic exacerbation has a strong genetic basis. Chromosome 17q21 Gasdermin B (GSDMB) region has been significantly associated with susceptibility and severity of childhood asthma, primarily in children who had prior respiratory virus infection. However, the mechanism by which how viral infection determines the asthmatic susceptibility among individuals with various genetic background is incompletely understood, which is the major focus of the proposal. Notably, the genotype of 17q21 asthma risk allele is associated with increased expression of GSDMB in human airway epithelial cells. Our unpublished work has demonstrated that GSDMB is not only sufficient but also required to promote IFNs signaling and induce expression of ISGs in human airway epithelial cells treated with RNA viruses or their analogue: poly (I:C). We now propose to characterize the biological and molecular mechanism by which GSDMB determines the risk for asthma following RNA virus infection. We have proposed a series of integrative and complementary in vitro, ex vivo and in vivo approaches to 1) dissect the molecular mechanisms by which GSDMB promotes IFNs signaling (Aim 1); 2) establish the Rhinovirus infection cellular model with prolonged inflammatory response induced by GSDMB in human bronchial epithelial cells with opposing genotypes of GSDMB (Aim 2); 3) in vivo consequence of prolonged and repetitive respiratory virus infection in mice with conditional and inducible expression of human GSDMB in airway epithelial cells (Aim 3). Our deep mechanistic understanding of such gene by environment interaction will illuminate novel treatment and perturbation strategy to prevent severe asthma exacerbation in susceptible subjects.