Abstract
Bordetellae, pathogenic to mammals, produce an immunomodulatory adenylate cyclase toxin–hemolysin (CyaA, ACT or AC-Hly) that enables them to overcome the innate immune defense of the host. CyaA subverts host phagocytic cells by an orchestrated action of its functional domains, where an extremely catalytically active adenylyl cyclase enzyme is delivered into phagocyte cytosol by a pore-forming repeat-in-toxin (RTX) cytolysin moiety. By targeting sentinel cells expressing the complement receptor 3, known as the CD11b/CD18 (αMβ2) integrin, CyaA compromises the bactericidal functions of host phagocytes and supports infection of host airways by Bordetellae. Here, we review the state of knowledge on structural and functional aspects of CyaA toxin action, placing particular emphasis on signaling mechanisms by which the toxin-produced 3′,5′-cyclic adenosine monophosphate (cAMP) subverts the physiology of phagocytic cells.
Highlights
Three species of the Gram-negative aerobic coccobacilli of the genus Bordetellae, B. pertussis, B. parapertussis and B. bronchiseptica, are pathogenic to mammals
Using murine RAW264.7 macrophages, we found that CyaA/cyclic adenosine monophosphate (cAMP) signaling through the protein kinase A (PKA) pathway activates by an as yet unknown mechanism the Src homology domain 2 containing protein tyrosine phosphatase (SHP) 1 that plays an important role in regulation of numerous receptor signaling processes in leukocytes [29]
The rapid waning of protection conferred by the current acellular pertussis vaccines, and the limited spectrum of antigens in these vaccines, appears as most worrisome [5]
Summary
Three species of the Gram-negative aerobic coccobacilli of the genus Bordetellae, B. pertussis, B. parapertussis and B. bronchiseptica, are pathogenic to mammals. The species B. pertussis is one of the few human-adapted pathogens and causes the respiratory infectious disease called pertussis, or whooping cough [1]. Pertussis remains the least-controlled vaccine preventable infectious disease. Hly moiety itself consists of four functional subdomains [7,10], comprising:. [11]; (ii) with an activation domain, with the two posttranslationally (ii) an activation the two posttranslationally acylated lysine residuesacylated [12,13]; lysine (iii) a residues [12,13]; RTX (iii) adomain receptor‐binding of ~40RTX typical calcium‐binding receptor-binding consisting of. ~40domain typical consisting calcium-binding nonapeptide repeats RTX [14]; nonapeptide repeats and (iv).
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