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bioRxiv · 10.1101/2025.01.13.632772

Infant RSV infection desensitizes β2-adrenergic receptor via CXCL11-CXCR7 signaling in airway smooth muscle

Zhao, C.·Taliento, A. E.·Belkin, E. M.·Fearns, R.·Lerou, P. H.·Ai, X.·Bai, Y.
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Abstract

RationaleAirflow obstruction refractory to {beta}2 adrenergic receptor ({beta}2AR) agonists is an important clinical feature of infant respiratory syncytial virus (RSV) bronchiolitis, with limited treatment options. This resistance is often linked to poor drug delivery and potential viral infection of airway smooth muscle cells (ASMCs). Whether RSV inflammation causes {beta}2AR desensitization in infant ASMCs is unknown. ObjectivesTo investigate the interaction of RSV inflammation with the {beta}2AR signaling pathway in infant ASMCs MethodsInfant precision-cut lung slices (PCLSs) and mouse pup models of RSV infection were subjected to airway physiological assays. Virus-free, conditioned media from RSV-infected infant bronchial epithelial cells in air-liquid interface (ALI) culture and nasopharyngeal aspirates (NPA) from infants with severe RSV bronchiolitis were collected and applied to infant PCLSs and ASMCs. Cytokines in these samples were profiled and assessed for the effects on {beta}2AR expression, cell surface distribution, and relaxant function in ASMCs. Measurements and Main ResultsConditioned media and NPA induced similar resistance to {beta}2AR agonists in ASMCs as RSV infection. Cytokine profiling identified CXCL11 as one of the most elevated signals following RSV infection. CXCL11 activated its receptor CXCR7 in a complex with {beta}2AR in ASMCs to promote {beta}2AR phosphorylation, internalization, and degradation. Blockade of CXCR7 partially restored airway relaxation in response to {beta}2AR agonists in infant PCLSs and mouse pup models of RSV infection. ConclusionsThe CXCL11-CXCR7 pathway plays a critical role in {beta}2AR desensitization in ASMCs during RSV infection and represents a potential therapeutic target in alleviating airflow obstruction in infant RSV bronchiolitis.

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Zhao, C., Taliento, A. E., Belkin, E. M., Fearns, R., Lerou, P. H., Ai, X., Bai, Y.. 2025-01-15. Infant RSV infection desensitizes β2-adrenergic receptor via CXCL11-CXCR7 signaling in airway smooth muscle. https://doi.org/10.1101/2025.01.13.632772

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