Human rhinovirus (HRV) infection of the upper airways is one of the strongest environmental risk factors for childhood asthma exacerbations. However, not all children experience an acute exacerbation in response to HRV infection. In fact, the asthmatic population is stratified into exacerbation-prone and exacerbation-resistant patients. Variability in patient cellular responses to virus infection could explain the exacerbation risk stratification observed in childhood asthmatics. The nasal airway epithelium is the primary site of HRV infection and replication, suggesting the importance of nasal epithelial responses to HRV. We hypothesize that heterogeneity exists in asthmatic airway pathobiological mechanisms (endotypes), some of which may predispose to exacerbations. Supporting this we find that high nasal gene expression levels of IL-13, a marker of the type 2-high asthma endotype, are associated with exacerbation risk. The response to virus of the airway epithelium is likely driven by the molecular state of the airway epithelium. Both endogenous immune (IL-13) and inhaled environmental exposures (environmental tobacco smoke (ETS)) can greatly alter the transcriptome profile of the airway epithelium. Additionally, recent studies have found genetic variants that affect airway gene expression predispose to childhood asthma exacerbations. Therefore, we hypothesize that an immune and/or environmentally ?primed? airway epithelium responds in a dysregulated way to viral infections, resulting in asthma exacerbations among genetically predisposed subjects. To test these hypotheses we propose the following aims:
Aim 1 : Determine if type 2 cytokine high and other nasal expression endotypes are associated with exacerbation-prone asthma and predict occurrence of asthma exacerbations. We will perform whole transcriptome sequencing (WTS) of nasal airway brushings from children with asthma that are exacerbation-prone (n=100), exacerbation-resistant (n=100), and healthy control subjects (n=100). We will identify genes, pathways, and expression endotypes that are associated with exacerbation- prone asthma.
Aim 2 : Determine how IL-13 and ETS stimuli modify the transcriptome response of nasal epithelial cells (NECs) to HRV infection and if these responses vary by exacerbation-prone asthma status. Air- liquid interface NEC cultures from Aim 1 donors will be treated with mock-stimulus, IL-13, ETS, HRV-A,-C or primed with IL-13 or ETS and then infected with HRV-A or -C. WTS gene expression data generated from these cultures will be used to identify differentially expressed genes by treatment. The treatment responses will be analyzed in a synergy/antagonism analysis to identify HRV infection responses that are perturbed by IL-13 or ETS pretreatment.
Aim 3 : We will identify in vivo airway epithelium expression quantitative trait loci (eQTL) variants in exacerbation-prone asthma genes. We will determine genetic variants that interact with immune/environmental stimulated airway epithelium to drive deleterious epithelial responses to HRV infection (response eQTLs). We will determine eQTL/reQTL variants that confer risk of exacerbation-prone asthma.

Public Health Relevance

Virus induced exacerbations of asthma are responsible for high levels of patient hospitalization and emergency room visits and significant economic burden. This proposal investigates new approaches for: 1) identifying environmental causes of exacerbation, 2) predicting patients who will exacerbate using minimally invasive techniques and 3) preventing infection by human rhinoviruses, which are the chief instigators of asthma exacerbation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Noel, Patricia
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National Jewish Health
United States
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Seibold, Max A (2018) Interleukin-13 Stimulation Reveals the Cellular and Functional Plasticity of the Airway Epithelium. Ann Am Thorac Soc 15:S98-S102
Evans, Christopher M; Seibold, Max A; Gerber, Anthony N (2018) SPDEFending the Lung through Mucin Expression. Am J Respir Cell Mol Biol 59:287-288
Mak, Angel C Y; White, Marquitta J; Eckalbar, Walter L et al. (2018) Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. Am J Respir Crit Care Med 197:1552-1564