Interleukin-22 controls RSV production in primary human airway epithelial cells by preserving cellular autophagy

Abstract

Abstract OBJECTIVE To study the ability of the host protective cytokine interleukin-22 (IL-22) to block productive infection of airway epithelial cells by Respiratory Syncytial Virus (RSV). BACKGROUND RSV infection can cause severe bronchiolitis and pneumonia in infants. However, no vaccine against RSV is currently available. RSV primarily infects both proximal and distal airways as well as alveolar epithelial cells in the lungs. IL-22 has mucosal-protective effects, known to preserve epithelial-barrier functions and promote host defense against pathogens. We, therefore, initiated studies to determine whether IL-22 can control RSV infection of airway epithelial cells (AECs). METHODS Primary human AECs differentiated under air-liquid interface (ALI) culture conditions were used for RSV infection (multiplicity of infection (MOI) 2) and then treated with IL-22 (50 ng/ml). 5-day old newborn C57BL/6 mice were intranasally infected with 1×106 PFU of RSV and then treated with an IL-22-Fc fusion protein (5 μg/mouse) intraperitoneally on day 3 p.i. Confocal imaging approach was utilized to determine co-localization of RSV and LC3B and to differentiate between autophagosomes and autolysosomes. RESULTS Treatment with IL-22 led to a significant decrease in viral load in primary human AECs as well as in vivo in mouse lungs. Confocal imaging and other approaches revealed subversion of the autophagic machinery by RSV for its own production, which was significantly inhibited by IL-22, thereby preserving autophagy in a STAT3 dependent manner. CONCLUSIONS IL-22 inhibits RSV production in both primary human airway epithelial cells and mouse lungs by preserving cellular autophagy thereby blocking hijacking of the autophagic apparatus by RSV.