Asthma occurs in ~12% of the US population, and rhinovirus (RV) is recognized as the principal virus producing the common cold syndrome worldwide. Unlike patients without asthma who generally develop upper respiratory symptoms during colds, asthmatics with an RV infection exhibit severe lower respiratory symptoms (e.g., cough, wheeze, shortness of breath). In fact, RV, especially species A and C, are associated with 60% to 80% of asthma exacerbations in children requiring treatment in the emergency department. Recent literature has shown that mutations in cadherin-related family member 3 (CDHR3), the receptor for RVC, increases susceptibility to RVC infection during exacerbations of asthma. RVA viruses similarly lead to exacerbations of asthma; however, a genetic link to disease remains unclear. Single nucleotide polymorphisms (SNPs) in 17q21/ORM1-like 3 (ORMDL3) have been associated with both exacerbation and development of asthma. Strikingly, ~60% of individuals with childhood onset asthma will have risk alleles at this locus. Recently, ORMDL3 was shown to regulate intercellular adhesion molecule 1 (ICAM1) expression in A549 cells. ICAM1 is the receptor utilized by RVA to infect epithelial cells. Taken together, this proposal speculates that gain of function (GOF) SNPs in the 17q21/ORMDL3 locus (risk alleles) modulating ICAM1 expression underlie the genetic susceptibility to RVA exacerbations in those with asthma. Evaluation of this hypothesis will occur in two specific aims that maximize research strengths of the Kennedy Laboratory.
For Aim 1, the Kennedy Laboratory will evaluate the effects of risk alleles on ICAM1 expression and downstream effects, including inflammatory cell infiltrates and mediators in children with asthma exacerbations.
Aim 2 will focus on a novel human precision-cut lung slice (PCLS) platform from donors with asthma and risk alleles. Evaluations of ICAM1 expression and inflammatory mediators, as well as measures of airway hyper-responsiveness (AHR) to carbachol after RV16 infection in PCLS with and without risk alleles underlie this aim. It is understood that RV does not replicate well in murine systems and that human cell cultures lack the ability to investigate physiologic responses of tissue and host immunity during viral infections. With the Kennedy Laboratory?s ability to prepare and maintain PCLS from human donors that preserve lung architecture and physiologic responses, our laboratory can examine, within the correct host and target tissue, immunologic mechanisms driving AHR, a surrogate for asthma exacerbations, in lung tissue from donors with asthma and risk alleles during RVA infections ex vivo. The project described will generate important data about the immunology of RVA disease in high-risk asthma populations and will establish a framework on which to conduct further translational investigations into the relevance of 17q21/ORMDL3 risk alleles, ICAM1, and RVA-induced immune responses that trigger RVA-induced asthma exacerbations.

Public Health Relevance

Based on the literature, 60% to 80% of children with asthma exacerbations presenting to the emergency department will have evidence of rhinovirus (RV), culpable for the exacerbation, and 60% of all children with asthma will have 17q21/ORMDL3 asthma risk alleles. Some of these single nucleotide polymorphisms (SNPs) (risk alleles) are gain of function and increase ORMDL3 expression, and, in turn, ORMDL3 has been shown to regulate ICAM1 expression, the receptor for RVA; thus, we hypothesize that asthma subjects with specific 17q21/ORMDL3 SNPs (risk alleles) will have increased ICAM1 expression leading to susceptibility to and increased symptoms during RVA-induced exacerbations of asthma. Study findings will begin to connect genetic risk for exacerbations of asthma related to RV infection, as well as provide a valuable resource for consideration of targeted therapeutics to ICAM1 or associated pathways in individuals with risk alleles.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Minnicozzi, Michael
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Arkansas Children's Hospital Research Institute
Little Rock
United States
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