# Long-term alteration of the airway epithelium after early life RSV infection

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $565,834

## Abstract

Severe RSV-bronchiolitis infection has been associated with the development of asthma later in
childhood. RSV is the primary cause of bronchiolitis in children worldwide, and it is considered the most impactful
risk factor for asthma development among causative pathogens. There is currently no vaccine approved, and
therapeutic options are limited. The mechanism by which early-life RSV (EL-RSV) infection predisposes to
asthma later in life is unknown. Our studies will investigate the mechanism behind asthma development after
EL-RSV infection by focusing on long-term lung epithelial alteration generated by epigenetic modification.
We will specifically investigate the role of the innate cytokines IL-1 and IL-33 in long-term lung epithelial
alteration since we had observed these cytokines highly upregulated during RSV infection. The present proposal
provides preliminary data demonstrating that EL-RSV infection generates long-term phenotypic changes in the
alveolar epithelial cell type II (AT2) through epigenetic modification in the Il33 gene and Ilr1 promoters. These
phenotypic changes in the lung epithelium after EL-RSV infection likely modify airway allergic reactions later in
life. Thus, we will address our hypothesis that EL-RSV infection generates long-lasting lung epithelium
alterations that impact lung responsiveness to allergens.
This leads to the upregulation of innate immune mediators, such as IL-33, that increase the risk of
developing airway allergies later in life. This hypothesis will be tested by the following specific aims: Aim 1-
To define whether EL-RSV infection generates long-lasting changes in the lung epithelium that leads to
subsequent allergic disease. We hypothesize that EL-RSV causes long-lasting changes in the lung
epithelium, which modify the lung epithelial cell's phenotype in the lung, leading to lung functional changes and
respiratory allergies later in life. Aim 2- To determine if RSV infection generates epigenetic modifications
in the lung epithelial cells that generate long-term alterations in the lung epithelium responsiveness. We
hypothesize that RSV infections drive lung epithelial cell long-term alteration by modifying the chromatin
organization and accessibility across the genome through histone modification. Aim 3- To identify the
mechanisms involved in generating the long-term alteration in the lung epithelium by focusing on the
positive feedback loop between IL-1 and IL-33 during RSV infection. Our working hypothesis is that the IL-
1/IL-33 upregulation during EL-RSV infection is critical for generating long-lasting modification in the lung
epithelium that may promote phenotypic alterations in the respiratory epithelium by epigenetic modification. We
hypothesize that EL-RSV infections drive airway epithelial cell alteration by modifying the organization and
accessibility of the chromatin across the genome by histone modification. Understanding these mechanisms will
be crucial for developing interventional ...

## Key facts

- **NIH application ID:** 11175776
- **Project number:** 1R56HL167750-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Wendy Fonseca Aguilar
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,834
- **Award type:** 1
- **Project period:** 2024-09-09 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11175776

## Citation

> US National Institutes of Health, RePORTER application 11175776, Long-term alteration of the airway epithelium after early life RSV infection (1R56HL167750-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11175776. Licensed CC0.

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