Impaired CC16-mediated host responses to rhinovirus in nasal epithelial cells from patients with asthma

Rhinovirus (RV) infections increase the risk for developing asthma and are the major trigger for disease exacerbations. CC16 levels are decreased in patients with asthma and inversely associated with inflammation and exacerbation frequency.

We sought to determine the impact of CC16 on the RV species A, type 1B (RV-A1B) infection in airway nasal epithelial cells in the context of asthma status.

Human nasal epithelial cells (HNECs) from participants with asthma and non-asthmatic participants in air-liquid interface culture were infected with RV-A1B, with and without recombinant CC16 (rCC16). Viral RNA and expression of host factors previously identified as associated with CC16 levels, including lysozyme, SPLUNC1, lactotransferrin, and surfactant protein D, were quantified by quantitative RT-PCR. Animal models and mouse tracheal epithelial cells (MTECs) sufficient and deficient in CC16 were infected with RV-A1B, with and without rCC16, to verify findings.

HNECs from participants with asthma (n = 7) had lower gene expression of CC16 and associated host defense factors under baseline conditions compared with HNECs from non-asthmatic participants (n = 7). Whereas RV infection increased host factors in HNECs from non-asthmatic participants, HNECs from participants with asthma failed to upregulate host factors in response to RV. rCC16 induced the expression of the host defense factors and reduced viral burden in HNECs from both non-asthmatic participants and participants with asthma, which was partly dependent on integrin α2β1, or VLA-2, interactions. CC16-deficient (CC16^-/-) mice had worse RV infection, more inflammation, and lower gene expression of host defense factors in their lungs compared with wild-type mice. Secreted protein levels were verified from apical washings of MTECs from CC16^-/- mice, which were significantly decreased compared with WT MTECs. Rescue studies in CC16^-/- mice by delivery of rCC16 during RV infection resulted in decreased inflammatory cell recruitment and infection.

Results suggest that CC16 reduces RV infection in epithelial cells by mediating the upregulation of host defense factors and that this mechanism may be defective in patients with asthma who have low levels of CC16.