# Viral and Host Determinants of Infant and Childhood Allergy and Asthma

> **NIH NIH U19** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $1,517,100

## Abstract

The long-term objective of this application is to define the relationship between infant respiratory syncytial virus
(RSV) infection and the host response that enables asthma inception, data needed to develop RSV and
asthma prevention strategies. There is abundant evidence that children who experience severe RSV during
infancy are at greater risk for developing asthma later in childhood; however, the host and viral determinants
that lead to asthma development are not known. In our prior funding cycle, we conducted a study considering
RSV infection in infancy as a natural quasi-random event and demonstrated that infant RSV infection, not only
severe infection, is associated with increased asthma risk, and that missing RSV infection during infancy
protects from asthma development. Furthermore, we demonstrated the mediating effect of infant RSV infection
on the developing airway microbiome and immune development and risk of wheeze, and in preliminary data,
the effect of RSV on long-term airway epithelial cell metabolism. Our overarching hypothesis for this proposal
is that age-dependent effects of infant RSV infection contribute to chronic respiratory disease through altering
DNA methylation (DNAm) of the airway epithelium, and airway epithelial metabolism and developmental
programming, and that identifying gene x RSV interactions will explain extremes of asthma susceptibility
following infant RSV infection. This proposal leverages rich data sets and birth cohorts to address these
hypotheses, and has the potential to greatly advance understanding of the mechanisms and developmental
processes underlying the effect of RSV on recurrent wheeze and asthma. To test these hypotheses we will use
a combination of two human natural quasi-randomization studies of infant RSV infection specifically designed
to assess effects of infant RSV infection on subsequent respiratory health and the airway epithelium, in vitro
models of RSV infection of nasal airway epithelial cells (NAECs), along with cutting edge-laboratory and
analytic approaches to integrate the resultant complex data. Project 2 leverages data from the INSPIRE cohort
that revealed that increased infant blood levels at birth of L-citrulline (L-CIT) were significantly associated with
decreased odds of infant bronchiolitis. These data suggested that higher blood levels of L-CIT at time of birth
protected against infant bronchiolitis and may protect against the development of asthma later in childhood.
We hypothesize that compared to regular diet (RD), an L-CIT supplemented diet (L-CITsd) fed to parents
during gestation and their offspring prevents severe RSV bronchiolitis in the offspring. Our preliminary data
strongly support this hypothesis and reveal that the L-CITsd decreased RSV-induced lung IL-13 expression,
reduced the frequency of lung IL-13 expressing ILC2, and restrained airways responsiveness. Further, L-
CITsd significantly decreased ILC2 expression of IL-13 when the cells were stimulated ex v...

## Key facts

- **NIH application ID:** 10262865
- **Project number:** 2U19AI095227-12
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ray Stokes Peebles
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,517,100
- **Award type:** 2
- **Project period:** 2011-08-04 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10262865

## Citation

> US National Institutes of Health, RePORTER application 10262865, Viral and Host Determinants of Infant and Childhood Allergy and Asthma (2U19AI095227-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10262865. Licensed CC0.

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