# Regulation of the Innate Immune Response by the Epithelium in Asthma

> **NIH NIH U19** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2020 · $307,888

## Abstract

Project Summary
Allergic sensitization is a significant risk factor for asthma, but allergic sensitization alone is insufficient for the
development of the asthma phenotype. Respiratory viruses are implicated in the development of asthma, and
serve as the most common trigger for asthma exacerbation. The airway epithelium serves as the primary
barrier between inhaled pathogens or environmental antigens and the host immune system, and is the major
target of many viruses. In this context, epithelial cells can function as components of the innate immune
system, serving as the orchestrator of innate immune responses. Prior work by our group and others
demonstrate that there are intrinsic differences in airway epithelial cells (AEC) from adults and children with
asthma, notable for alterations in the response to viral infection, and infiltration with innate immune cells such
as MCs (MCs). Our overall hypothesis is that AECs from subjects with asthma have an altered
response to respiratory viral infection that leads to the activation of innate immune cells that
propagate airway inflammation and hyperresponsiveness. The reasons that allergic sensitization
progresses to asthma in some individuals, and how allergic sensitization alters innate immune function remains
incompletely understood. We propose a “feed-forward” loop in which an intrinsically abnormal epithelial
response to viral infection leads to the generation of cytokines and chemokines that activate and reprogram
innate immune cells including MCs, recruited macrophages and innate lymphoid cells (ILC). We postulate that
these immune cells also feed forward by regulating epithelial-derived cytokine production. We will directly
address our hypothesis using primary AECs from children and adults with and without asthma and/or allergic
sensitization. We will use air-liquid-interface organotypic cell cultures to model respiratory viral infection in vitro
using co-culture models with human MCs and macrophages. In vivo models using allergic sensitization
followed by viral exacerbation will examine the contribution of epithelial-derived cytokines to the recruitment
and retention of MCs and recruited macrophages. In specific aim 1, we investigate the differences in innate
immune cells residing in the airways of subjects with asthma, relative to non-asthmatic control subjects with
and without allergic sensitization. We examine the contribution of innate cells as key sources of Th2 cytokines
in asthma. In specific aim 2, we determine how viral infection of the airway epithelium, acting through toll-like
receptor (TLR)3 and RIG-I-like receptor (RLR) signaling pathways, reprograms the phenotype and function of
innate immune cells. In specific aim 3, we use in vivo models to understand how epithelial-derived cytokines
act through MCs and recruited macrophages to regulate the development of airway inflammation and AHR.
The completion of these studies using phenotyped AECs will move the field forward through a be...

## Key facts

- **NIH application ID:** 9959316
- **Project number:** 5U19AI125378-05
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Teal S. Hallstrand
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $307,888
- **Award type:** 5
- **Project period:** 2016-07-15 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959316

## Citation

> US National Institutes of Health, RePORTER application 9959316, Regulation of the Innate Immune Response by the Epithelium in Asthma (5U19AI125378-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9959316. Licensed CC0.

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