β₂-adrenergic signaling controls neonatal respiratory syncytial virus infection by promoting viral clearance and airway protection.

Abstract

Respiratory syncytial virus (RSV) is the most common cause of acute bronchiolitis and pneumonia in children under 5 years of age. RSV infection is characterized by lung inflammation, viral expansion, and airway barrier destruction. The crosstalk between neurons and immune and non-immune cells develops from early life onwards. The lungs and airways are densely innervated by sympathetic neurons where they secrete the neurotransmitter noradrenaline (NA) at homeostasis and following injury in adult mice. NA, once secreted into the lungs, can act on immune and non-immune cells through β-adrenergic receptors (β-ARs). However, it is unknown whether NA-β-AR signaling axis regulates antiviral immunity during early-life infections. In a mouse model of neonatal RSV infection, we find that stimulation of adrenergic signaling via β₂-AR agonist increases viral clearance, anti-inflammatory responses, and disease recovery. By contrast, loss of sympathetic neurons and β₂-AR increases the RSV viral load and immunopathology in neonates. Stimulating β₂-AR signaling has several downstream effects, including reduced airway mucus secretion and protection from endothelial barrier disruption, which together prevent airway blockade, respiratory failure, and facilitate control of RSV infection. Collectively, our studies demonstrate that sympathetic neurons and β₂-AR signaling protect neonates from viral expansion and lung barrier breakdown, promoting antiviral defense.