# THE HUMAN INFANT AIRWAY EPITHELIUM AND RECURRENT WHEEZING AFTER RV AND RSV INFECTION

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $582,290

## Abstract

Rhinovirus (RV) and respiratory syncytial virus (RSV) cause common colds in healthy adults, but can cause
wheezing and respiratory distress in infants. This condition known as viral bronchiolitis is the top cause of
hospitalization in this age group. Infants hospitalized with RV or RSV bronchiolitis have an exceedingly high
risk (30-50%) of developing recurrent wheezing and asthma. Thus, understanding why humans are highly
susceptible to RV and RSV during infancy is needed for developing novel preventive and treatment strategies.
Importantly, using a model of the human infant airway epithelial cell (AEC) recently developed by our lab, we
provide novel evidence that relative to adult AECs, infant AECs produce higher levels of thymic stromal
lymphopoietin (TSLP), a cytokine that mediates virus-induced type 2 (T2) airway responses. We also find that
infant AECs exhibit: I) enhanced production and responsiveness to IL-1β, the most potent stimulus for TSLP
secretion; II) markedly increased IL-1β-induced nuclear translocation of NF-kB, the positive regulator of IL-1β
and TSLP transcription; and III) reduced transcriptional induction of IκBα, the inhibitor of NF-kB. These age-
related molecular differences suggest a novel mechanism of developmentally enhanced TSLP production in
the infant airway epithelium that may increase the risk of recurrent wheezing after RV or RSV bronchiolitis.
This is supported by our clinical studies demonstrating that: I) RV and RSV infections are associated with
elevated airway TSLP levels and parallel IL-1β secretion; II) airway TSLP levels are higher in infants
hospitalized with RV or RSV bronchiolitis who then developed recurrent wheezing than in infants who
recovered completely. These preliminary data has led us to propose mechanistic studies in human infant AECs
to test the central hypothesis that the human infant airway epithelium has enhanced NF-kB signaling
activation that promotes IL-1β-driven TSLP airway secretion and increases the risk for recurrent wheezing after
RV or RSV bronchiolitis. Three Specific Aims are proposed: Aim 1: To test the hypothesis that the human
infant airway epithelium exhibits enhanced NF-kB nuclear activation due to maturational differences in IkBα
synthesis and degradation. Aim 2: To test the hypothesis that the human infant airway epithelium has
enhanced TSLP responses to RV and RSV infections due to intrinsic maturational differences in the production
and responsiveness to IL-1β. Aim 3: To test the hypothesis that the development of recurrent wheezing in
human infants after the first episode of RV or RSV infection is associated with AEC maturational differences in
TSLP and IL-1β production due to enhanced NF-kB signaling activation. This proposal will move forward our
understanding of the AEC pathways involved in the pathogenesis of viral-induced wheezing in early life by
defining mechanisms underlying the maturational differences in pro-inflammatory responses between human
infant and adu...

## Key facts

- **NIH application ID:** 9898454
- **Project number:** 5R01HL141237-02
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Gustavo Nino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $582,290
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898454

## Citation

> US National Institutes of Health, RePORTER application 9898454, THE HUMAN INFANT AIRWAY EPITHELIUM AND RECURRENT WHEEZING AFTER RV AND RSV INFECTION (5R01HL141237-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898454. Licensed CC0.

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