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.

_{β 2} -肾上腺素受体 (β ₂ AR)的药理学激动作用通过激活腺苷酸环化酶产生环磷酸腺苷 (cAMP) 来诱导支气管扩张。β ₂ AR 激动剂通常是缓解哮喘患者急性气道阻塞的最有效策略，但当年轻患者的气道阻塞是由呼吸道合胞病毒 (RSV) 感染引发时，它们的效果要差得多。在这里，我们研究了 RSV 感染对源自儿童肺组织的原代人气道平滑肌细胞 (HASMC)中 β _{2 AR 的丰度和功能的影响。}我们发现 HASMC 的 RSV 感染导致 β _{2的蛋白水解切割}AR由蛋白酶体介导。RSV 感染还导致腺苷酸环化酶的 β ₂ AR 配体非依赖性激活，与未感染的对照细胞相比，导致 cAMP 合成减少。^{最后，由于胞质 Ca 2+}浓度增加，RSV 感染在体外引起更强的气道平滑肌细胞收缩。因此，我们的结果表明，RSV 感染同时诱导年轻患者功能性 β _{2 ARs 的丧失和有利于气道阻塞的多种途径的激活，净效应是抵消 β 2} AR 激动剂诱导的支气管扩张。这些发现不仅为所报道的β2缺乏临床疗效提供了潜在的机制_。用于治疗病毒引起的喘息的 AR 激动剂也为开发更精确的治疗策略开辟了道路。