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.