Respiratory syncytial virus induces β₂-adrenergic receptor dysfunction in human airway smooth muscle cells

Pharmacologic agonism of the β₂-adrenergic receptor (β₂AR) induces bronchodilation by activating the enzyme adenylyl cyclase to generate cyclic adenosine monophosphate (cAMP). β₂AR agonists are generally the most effective strategy to relieve acute airway obstruction in asthmatic patients, but they are much less effective when airway obstruction in young patients is triggered by infection with respiratory syncytial virus (RSV). Here, we investigated the effects of RSV infection on the abundance and function of β₂AR in primary human airway smooth muscle cells (HASMCs) derived from pediatric lung tissue. We showed that RSV infection of HASMCs resulted in proteolytic cleavage of β₂AR mediated by the proteasome. RSV infection also resulted in β₂AR ligand-independent activation of adenylyl cyclase, leading to reduced cAMP synthesis compared to that in uninfected control cells. Last, RSV infection caused stronger airway smooth muscle cell contraction in vitro due to increased cytosolic Ca²⁺ concentrations. Thus, our results suggest that RSV infection simultaneously induces loss of functional β₂ARs and activation of multiple pathways favoring airway obstruction in young patients, with the net effect of counteracting β₂AR agonist-induced bronchodilation. These findings not only provide a potential mechanism for the reported lack of clinical efficacy of β₂AR agonists for treating virus-induced wheezing but also open the path to developing more precise therapeutic strategies.