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

Abstract

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.

RSV-induced changes in a 3-dimensional organoid model of human fetal lungs

“…Postnatally, pharmacologic agonism of β2ARs typically induces bronchodilation by activating the adenylyl cyclase and generating cyclic adenosine monophosphate (cAMP), which in turn mediates smooth muscle relaxation through protein kinase A (PKA)-dependent mechanisms. However, we have recently shown that RSV infection results in proteolytic cleavage of β2AR, non-canonical activation of adenylyl cyclase impairing cAMP synthesis, and increased muscle contractility due to higher cytosolic calcium concentration, with the net effect of favoring airway obstruction and reducing the bronchodilator effect of β2AR agonists [ 16 ].…”

N-Acetyl-L-Cysteine Protects Airway Epithelial Cells during Respiratory Syncytial Virus Infection against Mucin Synthesis, Oxidative Stress, and Inflammatory Response and Inhibits HSPA6 Expression

“…RSV virus activity and load are related to the severity of the disease and also determine the degree of inflammation [ 18 ]. The anti-inflammatory property of NAC was confirmed in our study.…”

An overview on the RSV-mediated mechanisms in the onset of non-allergic asthma

“…Interestingly, the ß-2AR desensitization occurs in the absence of internalization or degradation of the β2-AR as it results from receptor uncoupling due to phosphorylation by GRK2 ( 60 ). More recently, Harford et al ( 61 ) investigated the density and activity of ß-2AR in primary HASM cells derived from pediatric lung tissue with RSV infection compared to non-infected control cells. Their findings showed that RSV induced simultaneously more effects, including a proteasome-mediated cleavage of ß-2AR, a ß-2AR ligand-independent activation of adenylyl-cyclase, and a decrease in cAMP release compared to the control cells, and, lastly, increased intracellular concentrations of Ca2+ resulting in ASM cells contraction ( 61 ).…”

“…More recently, Harford et al ( 61 ) investigated the density and activity of ß-2AR in primary HASM cells derived from pediatric lung tissue with RSV infection compared to non-infected control cells. Their findings showed that RSV induced simultaneously more effects, including a proteasome-mediated cleavage of ß-2AR, a ß-2AR ligand-independent activation of adenylyl-cyclase, and a decrease in cAMP release compared to the control cells, and, lastly, increased intracellular concentrations of Ca2+ resulting in ASM cells contraction ( 61 ). Lastly, another explanation for the lack of effectiveness of ß-2AR agonists in infants suffering from RSV infection could be due to the fact that RSV not only induces muscular constriction (bronchospasm) but also impacts the bronchiolar caliber, inducing lymphoid hyperplasia, edema, and mucous plugging, promoting an additional extrinsic compression.…”