MUC5B Expression Is Associated with Reduced Respiratory Syncytial Virus Infection and Pulmonary Inflammation

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease, particularly in infants and older adults. During RSV infection, excessive secretion and accumulation of gel-forming mucins can obstruct the small airways and contribute to pulmonary pathology. However, airway mucins also form a first-line barrier that traps inhaled pathogens and limits their access to the airway epithelium. Whether MUC5B, a major secreted mucin in the lower respiratory tract, influences RSV infection and associated pulmonary responses remains poorly understood. Here, we investigated the role of MUC5B during RSV infection using human A549 epithelial cells stably overexpressing MUC5B and female Muc5b-deficient mice. MUC5B overexpression significantly reduced intracellular RSV RNA levels following infection with the A2, Long, and B1 strains. In vivo, Muc5b−/− mice exhibited substantially higher pulmonary RSV RNA burdens at 5 days post-infection, whereas no significant genotype-dependent differences were detected in the nasal turbinates. Muc5b deficiency was also associated with more severe respiratory tract pathology and a higher proportion of pulmonary neutrophils after RSV infection. Eosinophil proportions increased after infection in both wild-type and Muc5b−/− mice, whereas the proportions of alveolar macrophages decreased and those of interstitial macrophages increased in both genotypes. Collectively, these findings suggest that, despite the established contribution of excessive mucus accumulation to airway obstruction, MUC5B also has a protective role during RSV infection. MUC5B may enhance pulmonary resistance to RSV by contributing to airway barrier function, reducing pulmonary viral burden, limiting tissue injury, and attenuating neutrophilic inflammation. These findings identify MUC5B as an important component of mucosal antiviral defense and broaden our understanding of how airway mucins influence susceptibility to RSV infection.