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Principal Investigator: JASON S DEBLEY
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $1,615,395
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Lower respiratory tract viral infections serve as the dominant trigger for the onset and progression of asthma.
Although asthma management has shifted towards targeting airway inflammation at all levels of the disease,
primarily with inhaled corticosteroids (ICS) and biologic therapies targeting type-2 (T2) inflammation, there is a
substantial burden of disease that is not responsive to these therapies. Specifically, a substantial portion of
individuals treated with ICS therapy have persistent T2 inflammation in their lower airways and a large and
growing portion of individuals with asthma have inflammation of the airways that is not T2 predominant (non-
T2). These related phenomena of persistent T2 (T2-high) and non-T2 inflammation in asthma are emerging as
the most common phenotypes in adults, and now make up a substantial portion of children with the disease.
The mechanisms responsible for persistent T2 and non-T2 inflammation are incompletely understood, but
there is strong evidence that the epithelium and epithelial-derived cytokines play a major role in the
immunology of asthma, and we have recently demonstrated that the epithelium is infiltrated with specific innate
immune cells that interact with the epithelium to propagate and regulate inflammation. Our central hypothesis
is that the airway epithelium serves as a central coordinator of the immune response to viral
respiratory tract infection in asthma. Further, airway epithelial cells (AECs) from T2-high and non-T2
individuals differentially interact with immune cells to support inflammation in a manner that can be
identified and targeted. We have an established program to isolate AECs from children and adults to
examine the function of these cells in asthma using a combination of organotypic cell culture models, often in
combination with immune cells. The primary goals of the Seattle Center are to identify primary alterations in
AECs in asthma, understand how AECs differ between T2-high and non-T2 individuals, and characterize
interactions between the epithelium and immune cells that are in close proximity. In Project 1, we examine the
underpinnings of persistent T2 inflammation mediated through mast cells and eosinophils acting in conjunction
with the epithelium and the components of this inflammation that are resistant to corticosteroids. In Project 2,
we examine the basis of interactions between the epithelium and macrophages, Th17 cells, and neutrophils
and how epithelial cells from each of the groups support inflammation through these cells. These projects are
supported by Pediatric and Adult Epithelial Cores (Core B) to isolate AECs from well phenotyped adults and
children and further examine connections between phenotype, genomics, genotype, and clinical outcome. The
studies are supported by an Advanced Bioinformatics Core (Core C) using state of the art single cell and
bulk RNA sequencing. These studies will facilitate the precise targeting of inflammation based on clinical
phenotype and epithelial endotype and a greater understanding of the basis of interactions between the
epithelium and immune cells that reside within the epithelium in asthma.
Terms: <0-11 years old><21+ years old><Adrenal Cortex Hormones><Adult><Adult Human><Affect><Asthma><Bio-Informatics><Bioinformatics><Biological Markers><Biological Response Modifier Therapy><Biological Therapy><Blood Eosinophil><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Bronchial Asthma><Bronchial-Dilating Agents><Bronchodilator Agents><Bronchodilators><Cell Body><Cell Communication><Cell Culture Techniques><Cell Function><Cell Interaction><Cell Physiology><Cell Process><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Child><Child Youth><Childhood><Children (0-21)><Chronic><Clinical><Corticoids><Corticosteroids><Disease><Disease Progression><Disorder><Disparity population><ED visit><ER visit><Emergency care visit><Emergency department visit><Emergency hospital visit><Emergency room visit><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Epithelial Cells><Epithelium><Genomics><Genotype><Goals><Heterogeneity><Hospital Admission><Hospitalization><Human><IFN><Immune><Immune response><Immune system><Immunes><Immunological response><Immunology><Individual><Individuals from minority><Individuals of minority><Infiltration><Inflammasome><Inflammation><Inhalation><Inhaling><Interferons><Lower respiratory tract structure><Lung><Lung Respiratory System><Macrophage><Marrow Eosinophil><Marrow Mast Cell><Marrow Neutrophil><Mediating><Methods><Minority Groups><Minority People><Minority Population><Minority individual><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Outcome><Persons><Phenotype><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Predisposition><Production><Proteomics><RNA Seq><RNA sequencing><RNAseq><Resistance><Respiratory Epithelium><Rhinovirus><Rhinovirus infection><Role><Sampling><Schools><Self-Help Groups><Severities><Single cell seq><Structure of respiratory epithelium><Subcellular Process><Support Groups><Susceptibility><Therapeutic><Tissue Basophils><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus Diseases><Work><adult youth><adulthood><airway epithelium><airway epithelium inflammation><airway inflammation><airway remodeling><asthma attack><asthma exacerbation><asthmatic><bio-markers><biologic marker><biological therapeutic><biological treatment><biologically based therapeutics><biomarker><biotherapeutics><biotherapy><burden of disease><burden of illness><cell culture><cell cultures><cell type><clinical phenotype><cytokine><disadvantaged group><disadvantaged individual><disadvantaged people><disadvantaged population><disadvantaged subgroup><disease burden><disparities across groups><disparity across subgroups><disparity among groups><disparity among subgroups><disparity between groups><disparity between subgroups><economic cost><eosinophil><exacerbation in asthma><exacerbation prone asthma><exacerbation prone asthmatic><group disparity><group inequality><group inequity><host response><immune system response><immunoresponse><inequalities among populations><inequalities between populations><inequalities in populations><inequality across populations><inequality among groups><inequality between groups><inequality in groups><inequities among populations><inequities between populations><inequities in populations><inequity across groups><inequity across populations><inequity between groups><inequity in groups><infected with Rhinovirus><intraepithelial><kids><lower respiratory tract><lumen dilator><lung function decline><mast cell><mastocyte><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pediatric><population inequality><population inequity><programs><pulmonary><pulmonary function decline><resistant><respiratory><respiratory inflammation><respiratory tract epithelium><respiratory tract inflammation><response><response to therapy><response to treatment><self help organization><single cell next generation sequencing><single cell sequencing><social role><subgroup disparity><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy response><transcriptome sequencing><transcriptomic sequencing><treatment response><treatment responsiveness><unequal group><unequal population><viral infection><viral respiratory infection><virus infection><virus-induced disease><young adult><young adulthood><youngster>