Deciphering the Mechanism Underlying Short- and Long-term Airway Hyperresponsiveness Following Early-life RSV Infection

Key Words: Respiratory Syncytial Virus, Airway Smooth Muscle Cell, Airway Hyperresponsiveness, Precision-Cut Lung Slice, Epithelial Air-Liquid Interface Culture, Mouse Models, Bruton Tyrosine Kinase

Respiratory Synthetical Virus (RSV) is the most common respiratory virus that causes young children sickness with cough, wheezing, and respiratory distress. In severe cases, sick babies need care in hospitals, even in intensive care units, with a breathing tube and ventilator to help them breathe. In addition, severe RSV infection at a young age increases the asthma risk in later childhood. Nevertheless, the only FDA-approved medication to prevent severe RSV infection is the monoclonal RSV antibody, such as Palivizumab or Nirsevimab. Their protective effect is promising but incomplete. Therefore, effective treatment of RSV infection remains a significant unmet need. Early-life RSV infection is known to induce airway inflammation and obstruction. Our research on RSV-induced airway obstruction focuses on airway smooth muscle cell (ASMC) dysfunction, as ASMCs are essential in regulating airway resistance. Our research objective is to explore how RSV infection modifies the ASMC function in early life, thus provoking abnormal airway constriction in the short and long term. To achieve the research goal, we established three models to replicate the airway epithelial RSV infection using infant and adult human epithelial culture, precision-cut lung slices (PCLSs), and BALB/c mouse pups and adults. These models reproduced worse RSV epithelial inflammation in early life than in adulthood. They also demonstrated that RSV did not infect ASMCs. Still, the inflammatory agents from RSV-infected epithelial cells could induce airway hyperresponsiveness (AHR) in neonates but not adults. In addition, RSV epithelial inflammation changed the gene expression profile in infant ASMCs, in particular, increasing the Bruton Tyrosine Kinase (BTK) gene expression. Building upon these findings, we propose an in-depth investigation to disclose the short and long-term ASM dysfunction induced by early-life RSV epithelial inflammation and the underlying mechanism through the abnormal BTK pathway in ASMCs. This research will inform how RSV epithelial infection causes airway obstruction in early life and its connection to asthma risk in later childhood. It will also lay the foundation for novel therapy to improve respiratory distress in acute RSV bronchiolitis and reduce the risk of childhood asthma.