Respiratory syncytial virus induces β(2)-adrenergic receptor dysfunction in human airway smooth muscle cells.

Pharmacologic agonism of the β(2)-adrenergic receptor (β(2)AR) induces bronchodilation by activating the enzyme adenylyl cyclase to generate cyclic adenosine monophosphate (cAMP). β(2)AR 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 β(2)AR 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 β(2)AR mediated by the proteasome. RSV infection also resulted in β(2)AR 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 Ca(2+) concentrations. Thus, our results suggest that RSV infection simultaneously induces loss of functional β(2)ARs and activation of multiple pathways favoring airway obstruction in young patients, with the net effect of counteracting β(2)AR agonist-induced bronchodilation. These findings not only provide a potential mechanism for the reported lack of clinical efficacy of β(2)AR agonists for treating virus-induced wheezing but also open the path to developing more precise therapeutic strategies.