Airway epithelium restricts penetration of inhaled pathogens into the underlying tissue and plays a crucial role in innate immune defense against respiratory infections. The whooping cough agent, Bordetella pertussis, adheres to ciliated cells of human airway epithelium and subverts its defense functions through the action of secreted toxins and other virulence factors. We have examined the impact of B. pertussis infection and of adenylate cyclase toxin (CyaA) action on the functional integrity of air-liquid interface (ALI)-cultured human bronchial epithelial cells. B. pertussis adhesion to the apical surface of polarized pseudostratified VA10 cell layers provoked disruption of tight junctions and caused drop o... More
Airway epithelium restricts penetration of inhaled pathogens into the underlying tissue and plays a crucial role in innate immune defense against respiratory infections. The whooping cough agent, Bordetella pertussis, adheres to ciliated cells of human airway epithelium and subverts its defense functions through the action of secreted toxins and other virulence factors. We have examined the impact of B. pertussis infection and of adenylate cyclase toxin (CyaA) action on the functional integrity of air-liquid interface (ALI)-cultured human bronchial epithelial cells. B. pertussis adhesion to the apical surface of polarized pseudostratified VA10 cell layers provoked disruption of tight junctions and caused drop of the trans-epithelial electrical resistance (TEER). The reduction of TEER depended on the capacity of the secreted CyaA toxin to elicit cAMP signaling in epithelial cells through its adenylyl cyclase enzyme activity. Both purified CyaA and cAMP signaling drugs triggered decrease of TEER of VA10 cell layers. Toxin-produced cAMP signaling caused actin cytoskeleton rearrangement and induced mucin 5AC production and IL-6 secretion, while inhibiting IL-17A-induced secretion of the IL-8 chemokine and of the antimicrobial peptide beta defensin-2. These results indicate that CyaA toxin activity compromises the barrier and innate immune functions of Bordetella-infected airway epithelia.
