LAUSR

The adenylate cyclase (CyaA) toxin is produced by Bordetella pertussis, the causative agent of whooping cough. The incidence of pertussis is currently increasing, and represents a global public health concern. Bordetella pertussis, a Gram-negative bacteria, has been identified by Jules Bordet and Octave Gengou who initially described “Le microbe de la coqueluche” in an article published in the Annales de l’Institut Pasteur in 1906. During the last decades, multidisciplinary approaches have contributed to improve our knowledge on CyaA, and showed that this toxin plays a crucial role in the early stages of respiratory tract colonization by disrupting the host immune response. CyaA is a 1706-residue-long, multi-domain, and bifunctional toxin containing a hemolysin and a calmodulin-activated adenylate cyclase producing supraphysiological levels of cAMP in host cells. This toxin is a unique well-characterized bacterial toxin able to translocate its catalytic domain directly across the plasma membrane of target cells. The molecular mechanism by which CyaA intoxicates host cells remains, however, largely unknown. Recent advances worldwide open new perspectives for both basic sciences and CyaA-based biotechnological applications, such as antigen delivery vehicles and CyaA-containing pertussis vaccines. These various aspects are discussed in this Special Issue of Toxins on the adenylate cyclase toxin. The first review from Nicole Guiso provides us with an overview on the properties of CyaA toxins produced by the bacteria from the genus Bordetella [1]. Due to the crucial contributions of the CyaA toxin at the early stages of whooping cough and its low variability, Nicole Guiso further discusses the relevance of CyaA as a vaccine antigen against whooping cough. Pertussis colonization of the host respiratory tract launches the primary innate immune defense. In their review, Giorgio Fedele and colleagues describe how CyaA is actively involved in the subversion of host immune responses by intoxicating a vast array of target cells [2]. In particular, the authors focus on the massive amounts of cAMP produced by CyaA in dendritic cells, alveolar macrophages, and neutrophils, leading to various effects and dramatically altering the host immune response. The ability of CyaA to deliver its catalytic domain into antigen presenting cells, such as in dendritic cells, has been exploited to engineer CyaA-based non-replicating recombinant proteins in which antigens are genetically inserted into the detoxified CyaA catalytic domain. Daniel Ladant and myself review these biotechnological applications he initiated in collaboration with Claude Leclerc in the early 1990s [3]. We illustrate the use of CyaA-based recombinant vaccines with data from clinical trials. This Special Issue then focuses on the molecular processes involved in CyaA biogenesis, membrane translocation, and the effects of cAMP intoxication. CyaA is produced as a protoxin, proCyaA, which is acylated in the bacteria before its secretion. Acylation is crucial for CyaA activation, i.e., to gain the ability to translocate its catalytic domain into target host cells. In a research article, Valérie Bouchez and colleagues characterize the nature of the acyl chains of CyaA toxins from various Bordetella isolates using state-of-the-art mass spectrometry methods [4]. The authors further analyzed