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Principal Investigator: Anny Xiaobo Zhou
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $640,287
Funding agency: National Heart Lung and Blood Institute
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 Our unpublished work has demonstrated that GSDMB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.
Terms: <0-11 years old><17q><17q21><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Affect><Age><Air><Airway Hyper-responsiveness><Anti-viral Response><Asthma><Asthma in Children><Binding><Biochemical><Biological><Bronchial Asthma><COVID-19 virus><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell model><Cells><Cellular model><Chemotactic Cytokines><Child><Child Youth><Childhood Asthma><Children (0-21)><Chromosome 17 Distal Arm><Chromosome 17 Long Arm><Chromosomes><CoV-2><CoV2><DNA><Data><Deoxyribonucleic Acid><Development><Double-Stranded RNA><Drug Targeting><Environmental Factor><Environmental Risk Factor><Epithelial Cells><Family member><GWA study><GWAS><Gene Transcription><Gene x Environment Interaction><GeneHomolog><Genes><Genetic><Genetic Transcription><Genotype><Goals><Guide RNA><GxE interaction><Health><Homolog><Homologous Chemotactic Cytokines><Homologous Gene><Homologue><Human><Hyperplasia><Hyperplastic><IFN><IFN activation><Immune response><Immunological response><In Vitro><Individual><Infant><Infection><Inflammation><Inflammatory><Inflammatory Response><Innate Immune Response><Intercrines><Interferon Activation><Interferons><Intracellular Communication and Signaling><Invaded><Knock-out><Knockout><Life><Liquid substance><Measures><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Mucous body substance><Mucus><Murine><Mus><Neonatal><Non-Polyadenylated RNA><Nucleic Acids><Pediatric asthma><Persons><Poly I-C><Polyinosinic-Polycytidylic Acid><Precision therapeutics><Predisposition><Predisposition gene><Production><Public Health><RNA><RNA Expression><RNA Gene Products><RNA Virus Infections><RNA Viruses><RNA viral infection><RSV infection><Respiratory Disease><Respiratory Epithelium><Respiratory Syncytial Virus Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory syncytial virus><Rhinovirus infection><Ribonucleic Acid><Risk><Risk-associated variant><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><School-Age Population><Series><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Structure of respiratory epithelium><Susceptibility><Susceptibility Gene><Testing><Time><Transcription><Transgenic Mice><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><Virus Replication><Wuhan coronavirus><ages><airway epithelium><airway epithelium inflammation><airway hyper-reactivity><airway hyperactivity><airway hyperreactivity><airway hyperresponsiveness><airway hypersensitivity><airway inflammation><analog><asthma attack><asthma exacerbation><asthma patient><asthmatic><asthmatic patient><biologic><biological signal transduction><bronchial epithelium><chemoattractant cytokine><chemokine><coronavirus disease 2019 virus><coronavirus disease-19 virus><developmental><dsRNA><environment effect on gene><environmental risk><exacerbation in asthma><exacerbation prone asthma><exacerbation prone asthmatic><fluid><gRNA><gene environment interaction><genome wide analysis><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome wide studies><genome-wide analysis><genome-wide identification><genomewide association scan><genomewide association studies><genomewide association study><hCoV19><host response><immune system response><immunoresponse><in vivo><inducible expression><inducible gene expression><infancy><infantile><infected with Rhinovirus><inhibitor><insight><kids><late life><liquid><mouse model><mucous><mucus hyper-secretion><mucus hypersecretion><murine model><nCoV2><neonatal mice><novel><overexpress><overexpression><pandemic><pandemic disease><poly I:C><poly IC><poly(I:C)><precision therapies><precision treatment><predisposing gene><prevent><preventing><promoter><promotor><respiratory><respiratory infection virus><respiratory inflammation><respiratory tract epithelium><respiratory tract inflammation><respiratory virus><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><school age><sensor><social><social role><susceptibility allele><susceptibility locus><susceptibility variant><unpublished works><viral RNA><viral infection><viral multiplication><viral replication><virus RNA><virus infection><virus multiplication><virus protein><virus-induced disease><whole genome association analysis><whole genome association studies><whole genome association study><youngster>