Abstract Rationale Rhinovirus (RV) is a major contributor to asthma onset and is one of the leading causes of asthma exacerbations. Club cell secretory protein (CC16), known for its anti-inflammatory properties and phospholipase A2 inhibitory activity, is significantly reduced in individuals with asthma, correlating with increased frequency of disease exacerbations. We previously discovered that CC16-mediated antiviral responses were impaired in nasal epithelial cells derived from asthma patients. Methods In this study, we investigated the role of CC16 in modulating RV infection in vivo using wild-type (WT) and CC16-deficient (CC16-/-) mice. Both whole animals and mouse tracheal epithelial cells (MTECs), cultured at air-liquid interface, were infected with RV-A1B. Recombinant CC16 (rCC16) was administered to RV-infected CC16-/- mice to assess therapeutic potential. Host defense markers including lysozyme, SPLUNC1, lactotransferrin, and surfactant protein-D were quantified via RT-qPCR and mass spectrometry. Viral burden was assessed using plaque assays and RT-qPCR. Results CC16-/- mice exhibited significantly higher RV loads and increased neutrophilic infiltration in the lungs. Notably, RV infection induced eosinophilic inflammation in CC16-/- but not in WT mice. Treatment with rCC16 reduced viral burden and reduced leukocyte recruitment in CC16-/- mice. Furthermore, MTECs from CC16-/- mice showed diminished expression of host defense factors and heightened susceptibility to RV infection compared to WT controls. Conclusion These findings in the mouse model deficient in CC16 mirror observations in airway epithelial cells derived from nasal brushes of asthmatic patients in which CC16 levels are diminished compared to those derived from non-asthma participants and support a protective role for CC16 in RV infection through the regulation of epithelial host defense mechanisms. Our data suggest that reduced CC16 levels may contribute to impaired antiviral responses in asthma, highlighting its potential as a therapeutic target. This abstract is funded by: NIH HL142769 and the Flinn Foundation
Tanyaratsrisakul et al. (Fri,) studied this question.