Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Respiratory syncytial virus (RSV) is a major cause of infant respiratory illness, including bronchiolitis and pneumonia.
• RSV infection primarily affects ciliated cells in the human bronchial epithelium, leading to significant morbidity in infants.

Purpose of the Study:

• To investigate age-dependent mechanisms regulating RSV interaction with the bronchial epithelium barrier.
• To identify molecular targets for therapeutic intervention against severe RSV infection in infants.

Main Methods:

• Utilized precision-cut lung slices and air-liquid interface cultures from infant and adult human donors.
• Employed single nuclear RNA-sequencing (snRNA-Seq) to analyze gene expression in response to RSV infection.
• Tested the efficacy of STAT3 activation and apoptotic inhibitors in infant models and a neonatal mouse model.

Main Results:

• Infant bronchial epithelium exhibited robust RSV spread and extensive apoptotic cell death, unlike adult epithelium.
• snRNA-Seq revealed age-related STAT3 activation insufficiency in infant ciliated cells, facilitating RSV spread via apoptotic cells.
• STAT3 activation and apoptosis blockade protected infant bronchial epithelium from severe RSV infection.
• Apoptotic inhibitor treatment reduced infection and inflammation in a neonatal mouse model.

Conclusions:

• Age-related STAT3-mediated antiapoptosis pathway insufficiency contributes to severe RSV disease in infants.
• Targeting the STAT3 pathway and apoptosis offers a promising therapeutic strategy for combating severe RSV infections in infants.