<i>CDHR3</i> Asthma-Risk Genotype Affects Susceptibility of Airway Epithelium to Rhinovirus C Infections

Abstract

CDHR3 (cadherin-related family member 3) is a transmembrane protein that is highly expressed in airway epithelia and the only known receptor for rhinovirus C (RV-C). A <i>CDHR3</i> SNP (rs6967330) with G to A base change has been linked to severe exacerbations of asthma and increased susceptibility to RV-C infections in young children. The goals of this study were to determine the subcellular localization of CDHR3 and to test the hypothesis that <i>CDHR3</i> asthma-risk genotype affects epithelial cell function and susceptibility to RV-C infections of the airway epithelia. We used immunofluorescence imaging, Western blot analysis, and transmission electron microscopy to show CDHR3 subcellular localization in apical cells, including expression in the cilia of airway epithelia. Polymorphisms in <i>CDHR3</i> rs6967330 locus (G→A) that were previously associated with childhood asthma were related to differences in CDHR3 expression and epithelial cell function. The rs6967330 A allele was associated with higher overall protein expression and RV-C binding and replication compared with the rs6967330 G allele. Furthermore, the rs6967330 A allele was associated with earlier ciliogenesis and higher <i>FOXJ1</i> expression. Finally, <i>CDHR3</i> genotype had no significant effects on membrane integrity or ciliary beat function. These findings provide information on the subcellular localization and possible functions of CDHR3 in the airways and link <i>CDHR3</i> asthma-risk genotype to increased RV-C binding and replication.