Pediatric and adult primary human airway epithelia exhibit similar rhinovirus C replication, innate responses, and expression of protein receptor.

Rhinovirus C (RV-C) infections during early life are strongly associated with severe wheezing illnesses, lower respiratory tract infections, recurrent hospitalizations, and subsequent asthma development. Cadherin-related family member 3 (CDHR3), the cellular receptor for RV-C, is expressed on the apical surface of ciliated airway epithelial cells, and increased surface expression of CDHR3 has been linked to enhanced viral binding and replication. These observations suggest that age-dependent differences in CDHR3 expression may contribute to the heightened clinical severity observed in young children. In this study, we investigated whether primary pediatric human airway epithelial (HAE) cultures exhibit increased CDHR3 surface expression, enhanced RV-C replication, and/or altered innate immune responses compared to adult HAE. Our findings demonstrate that pediatric and adult HAE have similar amounts of total cellular or surface CDHR3. Consistent with this observation, RV-C replication kinetics and virus-induced innate immune responses were comparable between pediatric and adult HAE. Together, these data indicate that intrinsic epithelial differences in CDHR3 abundance or antiviral signaling are unlikely to fully account for the age-dependent severity of RV-C-associated disease. These results refine our understanding of RV-C pathogenesis and suggest that additional factors, such as undeveloped humoral immunity to RV-C, immune cell interactions, airway microenvironment, or host developmental differences, may play a more prominent role in driving severe disease outcomes in early life.IMPORTANCERhinovirus C (RV-C) is a clinically significant pediatric respiratory pathogen associated with severe lower respiratory tract disease and an increased risk of asthma development later in childhood. Despite clear age-dependent differences in clinical severity, the underlying biological mechanisms remain poorly defined. Because cadherin-related family member 3 (CDHR3) serves as the cellular receptor for RV-C and is expressed on ciliated airway epithelial cells, variation in epithelial receptor abundance or antiviral responses has been proposed as a potential driver of increased viral burden in young children. To address this, we compared well-differentiated primary airway epithelial cultures derived from pediatric and adult donors. Our findings demonstrate that pediatric epithelial cells exhibit comparable CDHR3 cell surface abundance, RV-C replication dynamics, and virus-induced immune signaling relative to adult cells. These results suggest that factors beyond intrinsic epithelial susceptibility likely contribute to the heightened severity of RV-C disease in early life.