Related Experiment Video

Updated: May 7, 2026

An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection

Published on: December 10, 2013

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Infant respiratory syncytial virus infection disrupts β2 adrenergic airway relaxation via epithelial CXCL11

Caiqi Zhao1, Alice E Taliento1, Elise M Belkin1

  • 1Division of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, United States.

American Journal of Respiratory and Critical Care Medicine
|May 5, 2026
PubMed

Insights

Respiratory syncytial virus (RSV) bronchiolitis in infants impairs airway smooth muscle cell relaxation by upregulating CXCL11, which targets the ACKR3 receptor. This pathway desensitizes beta-2 adrenergic receptors (β2AR), suggesting new therapeutic targets for severe RSV.

Area of Science:

  • Respiratory viral infections
  • Airway smooth muscle physiology
  • Molecular signaling pathways

Background:

  • Infant respiratory syncytial virus (RSV) bronchiolitis is characterized by airflow obstruction unresponsive to beta-2 adrenergic receptor (β2AR) agonists.
  • The underlying mechanisms of this unresponsiveness are poorly understood, and effective treatments are lacking.

Purpose of the Study:

  • To investigate the impact of infant RSV infection on β2AR signaling in airway smooth muscle cells (ASMCs).
  • To elucidate the molecular mechanisms by which RSV affects β2AR function in ASMCs.

Main Methods:

  • Utilized complementary human and mouse models, including infant precision-cut lung slices (PCLSs), neonatal epithelial air-liquid interface (ALI) cultures, and mouse pups.
  • Assessed β2AR-mediated ASMC relaxation and performed cytokine profiling, bulk RNA sequencing, and β2AR expression/function assays.
  • Validated findings using nasopharyngeal aspirates (NPA) from infants with severe bronchiolitis.

Main Results:

  • RSV infection of infant bronchial epithelium induced cytokine secretion, impairing β2AR-mediated ASMC relaxation.
  • CXCL11 was identified as the key upregulated cytokine, signaling through ACKR3 to promote β2AR phosphorylation, internalization, and degradation.
  • Blockade of CXCL11 or ACKR3 restored β2AR responsiveness in RSV-infected infant lung tissues and tissues exposed to NPA from severe bronchiolitis patients.

Conclusions:

  • Infant RSV bronchiolitis utilizes the CXCL11-ACKR3 signaling pathway to desensitize β2AR in ASMCs.
  • Targeting the CXCL11-ACKR3 pathway presents a potential therapeutic strategy to enhance β2AR agonist efficacy in severe RSV bronchiolitis.
Abstract

Keywords:
ACKR3CXCL11airway smooth muscle cellsrespiratory syncytial virusβ2-adrenergic receptor desensitization

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