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Principal Investigator: JASON S DEBLEY
Organization: SEATTLE CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $860,375
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary: Asthma exacerbations among U.S children result in 640,000 emergency department visits,
280,000 hospitalizations, and 14 million missed school days annually. Type 2 (T2) cytokine-driven
inflammation characterizes the most common asthma endotype in children (T2-high) and is associated with
viral-triggered exacerbation risk. Although treatment of T2-high asthma with inhaled corticosteroids (ICS) or
biologics reduces exacerbation frequency in many patients, these treatments are suboptimal with millions of
viral-triggered exacerbations annually in the U.S. Furthermore, treatment of T2 inflammation does not alter the
natural history of asthma, and effective treatments for the 30% of children and adults with T2-low asthma are
lacking. Viral infections trigger most exacerbations in asthmatic children, of which human rhinoviruses (HRV)
are the most common. Some have reported deficient type I and III interferon (IFN) responses by asthmatic
AECs and postulated that deficient IFN responses predispose to exacerbations, however, this concept is
controversial as others have not observed deficient IFN responses to viruses by asthmatic AECs. We have
observed that greater AEC IFN expression at baseline or in response to ex vivo viral infection is associated
with lower lung function in asthmatic donors. Furthermore, in a recent longitudinal study of exacerbation-prone
asthmatic children higher baseline epithelial expression of a T2 gene module and lower expression of an IFN
module were associated with a shorter time to viral-triggered exacerbation.
In our cohort of well characterized asthmatic children, from whom we obtain bronchial AECs and conduct
mechanistic ex vivo experiments using organotypic models, we have observed marked heterogeneity in IFN
I/III responses to HRV and RSV infection, with greater HRV replication in AECs from exacerbation-prone
asthmatics. We recently observed greater production of the T2 alarmins TSLP and IL-33 by asthmatic AECs
with the lowest IFNλ responses to HRV, while AECs with the greatest IFNλ responses also had the greatest
production of T2-low/NLRP3 inflammasome-associated cytokines IL-1β and TNF-α. These observations,
inform our global hypotheses that the magnitude and kinetics of AEC IFN responses to HRV influence T2-high
and T2-low asthma endotypes, with moderate self-limited IFN responses essential to limit viral replication,
reduce exacerbation risk, and dampen T2 inflammation, while exaggerated IFN responses enhance the
NLRP3 inflammasome and production of T2-low cytokines (IL-1β, TNF-α), neutrophilic and inflammation,
airway remodeling, and lung function decline. Furthermore, we hypothesize that a common polymorphism in
the viral sensor IFIH1/MDA5 (rs1990760), recently associated with asthma, contributes to dysregulated AEC
IFN responses to HRV. Finally, we will use a humanized mouse expressing hICAM1 to allow HRV-A infection,
in the context of differential MDA5 function, to test in vivo the role of these pathways in HRV-A infection, T2-
high vs. T2-low airway inflammation, exacerbation, and airway remodeling.
Terms: <(TNF)-α><0-11 years old><21+ years old><APO2L><Adrenal Cortex Hormones><Adult><Adult Human><Affect><Alleles><Allelomorphs><Apo-2L><Apoptosis><Apoptosis Pathway><Asthma><Beta Proprotein Interleukin 1><Biological Agent><Biological Products><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Bronchial Asthma><Cachectin><Cell Body><Cells><Characteristics><Child><Child Youth><Children (0-21)><Clinical><Corticoids><Corticosteroids><Data><ED visit><ER visit><Emergency care visit><Emergency department visit><Emergency hospital visit><Emergency room visit><Epithelial Cells><Epithelium><Frequencies><Gene Expression><Genes><Genetic><Genetic Polymorphism><Genotype><Heterogeneity><Hospital Admission><Hospitalization><Human><IFIH1><IFN><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Immune Interferon><In vivo analysis><Incidence><Infection><Inflammasome><Inflammation><Inhalation><Inhaling><Interferon Gamma><Interferon Induced With Helicase C Domain 1><Interferon Type II><Interferons><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Kinetics><Knock-out><Knockout><Longitudinal Studies><MDA 5><Macrophage-Derived TNF><Marrow Neutrophil><Minor><Modeling><Modern Man><Monocyte-Derived TNF><Mouse Strains><Natural History><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Pathway interactions><Patients><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Preinterleukin 1 Beta><Prevalence><Production><Programmed Cell Death><Proteins><QTL><Quantitative Trait Loci><RSV infection><Reporting><Respiratory Epithelium><Respiratory Syncytial Virus Infections><Rhinovirus><Rhinovirus infection><Risk><Role><Schools><Structure of respiratory epithelium><System><TL2><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFSF10><TNFSF10 gene><TNFα><TRAIL><TSLP><TSLP gene><Testing><Thymic Stromal Lymphopoietin><Time><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Viral><Viral Diseases><Virus><Virus Diseases><Virus Replication><Work><adulthood><airway epithelium><airway epithelium inflammation><airway inflammation><airway remodeling><asthma attack><asthma exacerbation><asthmatic><asthmatic airway><biologics><biopharmaceutical><biotherapeutic agent><cohort><cytokine><decline in function><decline in functional status><effective therapy><effective treatment><exacerbation in asthma><exacerbation prone asthma><exacerbation prone asthmatic><experiment><experimental research><experimental study><experiments><functional decline><functional status decline><gain of function><gene locus><genetic locus><genomic location><genomic locus><human model><humanized mice><humanized mouse><in vivo><in vivo evaluation><in vivo testing><infected with Rhinovirus><insight><kids><lFN-Gamma><long-term study><longitudinal outcome studies><longterm study><lung function><lung function decline><melanoma differentiation associated gene 5><melanoma differentiation associated protein 5><model of human><mouse model><murine model><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><polymorphism><pulmonary function><pulmonary function decline><respiratory inflammation><respiratory tract epithelium><respiratory tract inflammation><response><sensor><social role><transcriptomics><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease><youngster>