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 Our unpublished work has demonstrated that GSDMB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.