# Regulation and Function of IL33 During Neonatal RSV Infection

> **NIH NIH R01** · LOUISIANA STATE UNIV A&M COL BATON ROUGE · 2020 · $444,192

## Abstract

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in infants worldwide; and human
epidemiological studies have identified age at initial RSV infection as an independent risk factor for the
development of childhood asthma. Our laboratory, and others, have used neonatal (i.e. ≤7d of age) mouse
models of infection to more closely mimic the interaction between RSV and the human infant immune system.
With these models, we demonstrated significant differences in the immune response to RSV of neonates
compared to adults. For example, neonatal mice mount a Th2-biased response to RSV infection as do human
infants. Reinfection of mice initially infected as neonates induces airway inflammation characterized by
neutrophils and eosinophils, mucus hyperproduction, and airways hyperreactivity, all symptoms of severe
human RSV disease. We previously found that much of these age-dependent responses were mediated by
increased levels of IL4Rα on neonatal myeloid dendritic cells (mDCs) and Th2 cells and by early signaling by
IL13. Here, our preliminary data demonstrate that this early IL13 is induced as a result of increased type II
innate lymphoid cells (ILC2s) and the increase in ILC2s is driven by rapidly elevated levels of IL33 in the
neonatal RSV-infected lung. This is correlated with defective IL1β production in RSV-infected neonates, which
we believe to be responsible for elevated IL33 (i.e. lack of negative regulation of IL33 by IL1β and/or caspase 1
in airway epithelial cells). Although IL33 has been studied extensively in other disease states, no study has
investigated the role of IL33 in RSV pathogenesis in a neonatal/infant immune system. Our findings lead to our
current, novel hypothesis that inchoate IL1β production by neonatal AECs during RSV infection results in
excessive pulmonary IL33 that activates DCs promoting Th2-biased immunopathogenesis. We will
explore the validity of this hypothesis using unique sample sets from human infant RSV infection cohorts and
age-relevant mouse models through the following specific aims. Aim 1 will demonstrate that neonatal
progenitor airway epithelial cells (AECs) orchestrate RSV immunopathogenesis via IL33. We will also
demonstrate that IL33 is predictive of RSV disease severity in infants. Aim 2 will determine if age-related
differences in IL1β responses by AECs are responsible for increased IL33 levels and the production of more
active forms of IL33 in response to neonatal RSV using innovative methodologies for targeted quantitative
investigation of IL33 form variants. Aim 3 will identify mechanisms whereby IL33 directly activates pulmonary
DCs to prime naïve CD4+ T cells to induce Th2-biased responses. The concept of age-dependent regulation of
IL33 presented here is novel and will provide molecular mechanisms responsible for the human infant immune
response to RSV. In addition, the data derived from these studies are expected to have a positive paradigm-
shifting impact in understanding s...

## Key facts

- **NIH application ID:** 9975681
- **Project number:** 5R01AI090059-11
- **Recipient organization:** LOUISIANA STATE UNIV A&M COL BATON ROUGE
- **Principal Investigator:** Stephania A Cormier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,192
- **Award type:** 5
- **Project period:** 2011-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975681

## Citation

> US National Institutes of Health, RePORTER application 9975681, Regulation and Function of IL33 During Neonatal RSV Infection (5R01AI090059-11). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9975681. Licensed CC0.

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