Abstract
The mucus layer protects airway epithelia from damage by noxious agents. Intriguingly, Bordetella pertussis bacteria provoke massive mucus production by nasopharyngeal epithelia during the initial coryza-like catarrhal stage of human pertussis and the pathogen transmits in mucus-containing aerosol droplets expelled by sneezing and post-nasal drip-triggered cough. We investigated the role of the cAMP-elevating adenylate cyclase (CyaA) and pertussis (PT) toxins in the upregulation of mucin production in B. pertussis-infected airway epithelia. Using human pseudostratified airway epithelial cell layers cultured at air–liquid interface (ALI), we show that purified CyaA and PT toxins (100 ng/mL) can trigger production of the major airway mucins Muc5AC and Muc5B. Upregulation of mucin secretion involved activation of the cAMP response element binding protein (CREB) and was blocked by the 666-15-Calbiochem inhibitor of CREB-mediated gene transcription. Intriguingly, a B. pertussis mutant strain secreting only active PT and producing the enzymatically inactive CyaA-AC– toxoid failed to trigger any important mucus production in infected epithelial cell layers in vitro or in vivo in the tracheal epithelia of intranasally infected mice. In contrast, the PT– toxoid-producing B. pertussis mutant secreting the active CyaA toxin elicited a comparable mucin production as infection of epithelial cell layers or tracheal epithelia of infected mice by the wild-type B. pertussis secreting both PT and CyaA toxins. Hence, the cAMP-elevating activity of B. pertussis-secreted CyaA was alone sufficient for activation of mucin production through a CREB-dependent mechanism in B. pertussis-infected airway epithelia in vivo.
Highlights
Infections by the Gram-negative bacterium Bordetella pertussis cause the highly contagious respiratory illness called pertussis, or whooping cough, which used to be the primary cause of infant mortality prior to global introduction of whole cell-based pertussis vaccines seven decades ago [1]
Due to the switch to less reactogenic and less efficient acellular pertussis vaccines some two decades ago, B. pertussis circulation and whooping cough disease have recently resurged in most developed countries and undiagnosed mild disease and asymptomatic B. pertussis infections are common in highly aP-vaccinated populations [2,3,4]
Since Gαi/o inactivation by pertussis toxin (PT) can yield increased cAMP levels, we investigated if PT triggers mucin production in airway epithelial cells
Summary
Infections by the Gram-negative bacterium Bordetella pertussis cause the highly contagious respiratory illness called pertussis, or whooping cough, which used to be the primary cause of infant mortality prior to global introduction of whole cell-based pertussis vaccines seven decades ago [1]. The B. pertussis bacterium is well armed for immune escape and produces the potently immunosuppressive adenylate cyclase toxin (CyaA) and the more notoriously known pertussis toxin (PT), which both play a major role in hijacking of host immune response [6]. The 1706 residue-long CyaA polypeptide comprises an N-terminal cell-invasive adenylate cyclase (AC) enzyme domain of 384 residues that is linked to a 1322 residue-long pore-forming RTX hemolysin/cytolysin (Hly) moiety [11,12]. The Hly moiety binds with high affinity the CD11b subunit of the CD11b/CD18 integrin that serves as complement receptor 3 (CR3, αM β2 , or Mac-1)
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