# Early Life Rhinovirus Infection and Childhood Asthma

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $453,607

## Abstract

Project Summary
Birth cohort studies have found significant associations between early-life wheezing-associated respiratory
tract infections and the development of asthma in children up to 13 years of age. These studies suggest that
early life respiratory tract infections have a direct effect on lung and/or immune cell development and the risk of
asthma. To determine possible mechanisms, we established a mouse model of early-life RV infection. Infection
of 6 day-old mice, but not mature mice, induces long-lasting mucous metaplasia, eosinophilic inflammation and
airways hyperresponsiveness (AHR) which is associated with type 2 innate lymphoid cell (ILC2) expansion and
dependent on IL-13, IL-25 and IL-33. For this renewal application, we have developed preliminary data
showing that early-life RV infection increases the number of airway IL-25+ DCLK1+ brush cells, providing a
mechanism for a persistent ILC2-dependent asthma-like phenotype. In addition, we have found that, in
immature mice, activation of the NLRP3 inflammasome and IL-1β maturation inhibits type 2 cytokine
expression and mucous metaplasia. In this proposal, we will test the general hypothesis that, following early-
life RV infection, development of ILC2-dependent type 2 airway inflammation and mucous metaplasia
represents a balance between tuft cell RV-induced IL-25 signaling (promotes the phenotype) and NLRP3-
dependent IL-1β signaling (suppresses the phenotype). To test this, we propose the following Aims:
 Specific Aim 1. Determine the contribution of airway brush (tuft) cells to viral-induced IL-25
production. We hypothesize that: 1) early-life RV infection stimulates a persistent increase in the number of
IL-25-producing airway tuft cells; 2) tuft cells are required for RV-induced ILC2 expansion, mucous metaplasia
and AHR; 3) RV-induced IL-25 and IL-13 production (by ILC2s and M2 polarized macrophages) constitute a
feed-forward mechanism for tuft cell development.
 Specific Aim 2. Determine the role of IL-1β on the development of RV-induced mucous metaplasia
and AHR. We hypothesize that: 1) in immature mice, RV-induced, NLRP3 inflammasome-dependent IL-1β
production suppresses the asthma-like phenotype; 2) IL-1β inhibits epithelial cell innate cytokine expression;
and 3) LPS and dog-associated house dust each attenuate development of the mucous metaplasia phenotype
by stimulating inflammasome priming and activation.
 Specific Aim 3. Determine the effects of early-life RV-C infection. We hypothesize that: 1) compared
to RV-A, RV-C infection of 6 day-old mice induces more type 2 inflammation, mucous metaplasia and AHR; 2)
RV-C induces greater expansion of tuft cells; 3) RV-C elicits inflammasome priming but not activation, thereby
permitting greater and more long-lasting type 2 cytokine expression and mucous metaplasia.
 Immature mice and infants with respiratory viral infections will be studied. Completion of the proposed work
will provide new insight into the pathogenesis of asthma...

## Key facts

- **NIH application ID:** 10048490
- **Project number:** 2R01AI120526-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Marc B. Hershenson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,607
- **Award type:** 2
- **Project period:** 2015-07-03 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048490

## Citation

> US National Institutes of Health, RePORTER application 10048490, Early Life Rhinovirus Infection and Childhood Asthma (2R01AI120526-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10048490. Licensed CC0.

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