BMC Seminar Thursday, 17th December at 12:00 Room 343 Læknagarður
Speaker: Nikhil N. Kulkarni, PhD student supervised by Prof. Guðmundur H. Guðmundsson, Life and environmental sciences, School of Engineering and Natural Sciences, University of Iceland
Title: Bordetella adenylate cyclase toxin manipulates the epithelial innate defense mechanisms and disrupts the barrier function of differentiated lung epithelial cells.
Abstract: The adenylate cyclase toxin (CyaA) plays a key role in virulence of Bordetella pertussis. CyaA penetrates various host cells and subverts their immune functions through unregulated conversion of cytosolic ATP into the signalling molecule adenosine 3', 5'-cyclic monophosphate (cAMP). We examined here the effects of CyaA toxin action on respiratory epithelium using the air-liquid interface (ALI) differentiated human bronchial epithelial cell line VA10. While the non-enzymatic CyaA AC- toxoid unable to elevate cAMP had no effects, the treatment of ALI-differentiated VA10 cells with CyaA from the basolateral side lead to enhanced mucin Muc5AC expression and disruption of the physical barrier integrity. This was characterized by decreased TER due to suppression of ZO-1 and occludin production and disintegration of tight junctions. At the same time expression of genes for antimicrobial polypeptides like cathelicidin, human beta defensin-1, lactoferrin and lysozyme was enhanced, while expression of the human beta defensin-2 (hBD2) gene was strongly decreased. The mRNA for the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-8 was downregulated, while expression of interleukin-6 and interleukin-10 genes was enhanced in 1 h and 6 h of CyaA toxin treatment, respectively. CyaA toxin-catalyzed synthesis of cAMP thus compromised the epithelial barrier integrity and yielded immunomodulatory cytokine signalling of ALI-differentiated bronchial epithelial cells.