# Models of rhinovirus-C respiratory infection and asthma

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $422,063

## Abstract

PROJECT SUMMARY
Accumulating evidence indicates that infections with a newly-discovered species of rhinovirus, RV-C, are asso-
ciated with severe respiratory tract infections and asthma exacerbations often requiring hospitalization. In addi-
tion, recent data suggest a possible role for early-life RV-C infections in asthma development.
 Despite increasing recognition of RV-C as a cause of asthmatic disease, virtually nothing is known about
the pathogenesis of RV-C infections. To accomplish this, we infected mice with RV-C15 (the RV-C15 infec-
tious clone and HeLa-E8 cells overexpressing a variant of the human RV-C receptor, cadherin related family
member 3, were obtained from James Gern, University of Wisconsin). Our pilot studies show that RV-C15-
infected mice show increased type 2 cytokine and mucin gene expression, BAL eosinophils and lineage-nega-
tive, CD25+, CD127+ type 2 innate lymphoid cells (ILC2s) compared to RV-A1B-infected mice. In addition, pi-
lot studies from children with natural RV-C infections show increased type 2 cytokine production.
 In this application, we will test the general hypothesis that, after RV-C infection, airway innate cytokine ex-
pression drives ILC2 expansion and development of eosinophilic inflammation and mucous metaplasia. To test
this hypothesis, we propose the following Specific Aims:
 Specific Aim 1. Determine the contribution of epithelial-derived innate cytokines to RV-C15-induced
eosinophilic airway inflammation and hyperresponsiveness (AHR). We hypothesize that: 1) compared to
RV-A, RV-C infection of mature mice induces greater lung expression of innate cytokines (IL-25, IL-33, TSLP);
2) IL-25 is produced by doublecortin-like kinase (DCLK)-1-positive airway tuft cells; 3) innate cytokines are re-
quired for eosinophilic inflammation; 4) RV-C engagement of CDHR3 activates distinct signaling pathways
leading to innate cytokine expression.
 Specific Aim 2. Determine the contribution of lung ILC2s and macrophages to RV-C-induced airway
inflammation and AHR. We hypothesize that: 1) RV-C infection of mature mice induces innate cytokine-de-
pendent expansion of ILC2s; 2) ILC2s promote eosinophilic inflammation, macrophage polarization and AHR;
3) house dust mite (HDM) and RV-C have additive effects on eosinophilic inflammation and AHR; 4) ILC2s
convey corticosteroid resistance; and 5) nasal aspirates from human subjects infected with RV-C show in-
creased expression of type 2 cytokines and ILC2s compared to samples from RV-A-infected subjects.
 Specific Aim 3. Determine the effects of early-life RV-C infection on the established asthma pheno-
type. We have found that RV-A1B infection of six day-old mice, but not mature mice, induces long-lasting mu-
cous metaplasia and AHR which is dependent on IL-13-producing ILC2s. We hypothesize that: 1) RV-C infec-
tion of 6 day-old mice induces greater and more long-lasting mucous metaplasia than RV-A; 2) early-life RV-C
infection increases the number of IL-25-producin...

## Key facts

- **NIH application ID:** 10093541
- **Project number:** 1R01AI155444-01
- **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:** $422,063
- **Award type:** 1
- **Project period:** 2020-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093541

## Citation

> US National Institutes of Health, RePORTER application 10093541, Models of rhinovirus-C respiratory infection and asthma (1R01AI155444-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10093541. Licensed CC0.

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