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Adenylate Cyclase (CyaA) Toxin
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Adenylate Cyclase (CyaA) Toxin

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (15 November 2017) | Viewed by 77610

Special Issue Editor

Dr. Alexandre Chenal

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Guest Editor
Unité de Biochimie des Interactions Macromoléculaires, CNRS UMR 3528, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris cedex 15, France
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

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, was 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 few 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 calmodulin-activated adenylate cyclase and a hemolysin. This toxin is the 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.

Dr. Alexandre Chenal
Guest Editor

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Keywords

  • Adenylate cyclase
  • CyaA toxin
  • bacterial toxin
  • repeat in toxin
  • RTX protein
  • cell receptor
  • membrane translocation
  • calmodulin-stimulated enzyme, cAMP
  • pertussis vaccine
  • antigen delivery vehicle
  • protein engineering
  • innate immune response
  • alveolar macrophage

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

3 pages, 181 KiB  
Editorial
An Introduction to the Toxins Special Issue on the Adenylate Cyclase Toxin
by Alexandre Chenal
Toxins 2018, 10(10), 386; https://doi.org/10.3390/toxins10100386 - 24 Sep 2018
Cited by 1 | Viewed by 2546
Abstract
n/a Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)

Research

Jump to: Editorial, Review

1381 KiB  
Communication
Site I Inactivation Impacts Calmodulin Calcium Binding and Activation of Bordetella pertussis Adenylate Cyclase Toxin
by Christian W. Johns and Natosha L. Finley
Toxins 2017, 9(12), 389; https://doi.org/10.3390/toxins9120389 - 30 Nov 2017
Cited by 2 | Viewed by 4653
Abstract
Site I inactivation of calmodulin (CaM) was used to examine the importance of aspartic acid 22 at position 3 in CaM calcium binding, protein folding, and activation of the Bordetella pertussis adenylate cyclase toxin domain (CyaA-ACD). NMR calcium titration experiments showed that site [...] Read more.
Site I inactivation of calmodulin (CaM) was used to examine the importance of aspartic acid 22 at position 3 in CaM calcium binding, protein folding, and activation of the Bordetella pertussis adenylate cyclase toxin domain (CyaA-ACD). NMR calcium titration experiments showed that site I in the CaM mutant (D22A) remained largely unperturbed, while sites II, III, and IV exhibited calcium-induced conformational changes similar to wild-type CaM (CaMWt). Circular dichroism analyses revealed that D22A had comparable α-helical content to CaMWt, and only modest differences in α-helical composition were detected between CaMWt-CyaA-ACD and D22A-CyaA-ACD complexes. However, the thermal stability of the D22A-CyaA-ACD complex was reduced, as compared to the CaMWt-CyaA-ACD complex. Moreover, CaM-dependent activity of CyaA-ACD decreased 87% in the presence of D22A. Taken together, our findings provide evidence that D22A engages CyaA-ACD, likely through C-terminal mediated binding, and that site I inactivation exerts functional effects through the modification of stabilizing interactions that occur between N-terminal CaM and CyaA-ACD. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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2020 KiB  
Article
Membrane-Active Properties of an Amphitropic Peptide from the CyaA Toxin Translocation Region
by Alexis Voegele, Orso Subrini, Nicolas Sapay, Daniel Ladant and Alexandre Chenal
Toxins 2017, 9(11), 369; https://doi.org/10.3390/toxins9110369 - 14 Nov 2017
Cited by 21 | Viewed by 5887
Abstract
The adenylate cyclase toxin CyaA is involved in the early stages of infection by Bordetella pertussis, the causative agent of whooping cough. CyaA intoxicates target cells by a direct translocation of its catalytic domain (AC) across the plasma membrane and produces supraphysiological [...] Read more.
The adenylate cyclase toxin CyaA is involved in the early stages of infection by Bordetella pertussis, the causative agent of whooping cough. CyaA intoxicates target cells by a direct translocation of its catalytic domain (AC) across the plasma membrane and produces supraphysiological levels of cAMP, leading to cell death. The molecular process of AC translocation remains largely unknown, however. We have previously shown that deletion of residues 375–485 of CyaA selectively abrogates AC translocation into eukaryotic cells. We further identified within this “translocation region” (TR), P454 (residues 454–484), a peptide that exhibits membrane-active properties, i.e., is able to bind and permeabilize lipid vesicles. Here, we analyze various sequences from CyaA predicted to be amphipatic and show that although several of these peptides can bind membranes and adopt a helical conformation, only the P454 peptide is able to permeabilize membranes. We further characterize the contributions of the two arginine residues of P454 to membrane partitioning and permeabilization by analyzing the peptide variants in which these residues are substituted by different amino acids (e.g., A, K, Q, and E). Our data shows that both arginine residues significantly contribute, although diversely, to the membrane-active properties of P454, i.e., interactions with both neutral and anionic lipids, helix formation in membranes, and disruption of lipid bilayer integrity. These results are discussed in the context of the translocation process of the full-length CyaA toxin. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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2671 KiB  
Article
Characterization of Post-Translational Modifications and Cytotoxic Properties of the Adenylate-Cyclase Hemolysin Produced by Various Bordetella pertussis and Bordetella parapertussis Isolates
by Valérie Bouchez, Thibaut Douché, Mélody Dazas, Sophie Delaplane, Mariette Matondo, Julia Chamot-Rooke and Nicole Guiso
Toxins 2017, 9(10), 304; https://doi.org/10.3390/toxins9100304 - 26 Sep 2017
Cited by 6 | Viewed by 5149
Abstract
Bordetella pertussis and Bordetella parapertussis are the causal agents of whooping cough in humans. They produce diverse virulence factors, including adenylate cyclase-hemolysin (AC-Hly), a secreted toxin of the repeat in toxins (RTX) family with cyclase, pore-forming, and hemolytic activities. Post-translational modifications (PTMs) are [...] Read more.
Bordetella pertussis and Bordetella parapertussis are the causal agents of whooping cough in humans. They produce diverse virulence factors, including adenylate cyclase-hemolysin (AC-Hly), a secreted toxin of the repeat in toxins (RTX) family with cyclase, pore-forming, and hemolytic activities. Post-translational modifications (PTMs) are essential for the biological activities of the toxin produced by B. pertussis. In this study, we compared AC-Hly toxins from various clinical isolates of B. pertussis and B. parapertussis, focusing on (i) the genomic sequences of cyaA genes, (ii) the PTMs of partially purified AC-Hly, and (iii) the cytotoxic activity of the various AC-Hly toxins. The genes encoding the AC-Hly toxins of B. pertussis and B. parapertussis displayed very limited polymorphism in each species. Most of the sequence differences between the two species were found in the C-terminal part of the protein. Both toxins harbored PTMs, mostly corresponding to palmitoylations of the lysine 860 residue and palmoylations and myristoylations of lysine 983 for B. pertussis and AC-Hly and palmitoylations of lysine 894 and myristoylations of lysine 1017 for B. parapertussis AC-Hly. Purified AC-Hly from B. pertussis was cytotoxic to macrophages, whereas that from B. parapertussis was not. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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2542 KiB  
Article
Functional Contributions of Positive Charges in the Pore-Lining Helix 3 of the Bordetella pertussis CyaA-Hemolysin to Hemolytic Activity and Ion-Channel Opening
by Chattip Kurehong, Chalermpol Kanchanawarin, Busaba Powthongchin, Panchika Prangkio, Gerd Katzenmeier and Chanan Angsuthanasombat
Toxins 2017, 9(3), 109; https://doi.org/10.3390/toxins9030109 - 16 Mar 2017
Cited by 6 | Viewed by 5490
Abstract
The Bordetella pertussis CyaA-hemolysin (CyaA-Hly) domain was previously demonstrated to be an important determinant for hemolysis against target erythrocytes and ion-channel formation in planar lipid bilayers (PLBs). Here, net-charge variations in the pore-lining helix of thirteen related RTX cytolysins including CyaA-Hly were revealed [...] Read more.
The Bordetella pertussis CyaA-hemolysin (CyaA-Hly) domain was previously demonstrated to be an important determinant for hemolysis against target erythrocytes and ion-channel formation in planar lipid bilayers (PLBs). Here, net-charge variations in the pore-lining helix of thirteen related RTX cytolysins including CyaA-Hly were revealed by amino acid sequence alignments, reflecting their different degrees of hemolytic activity. To analyze possible functional effects of net-charge alterations on hemolytic activity and channel formation of CyaA-Hly, specific mutations were made at Gln574 or Glu581 in its pore-lining α3 of which both residues are highly conserved Lys in the three highly active RTX cytolysins (i.e., Escherichia coli α-hemolysin, Actinobacillus pleuropneumoniae toxin, and Aggregatibacter actinomycetemcomitans leukotoxin). All six constructed CyaA-Hly mutants that were over-expressed in E. coli as 126 kDa His-tagged soluble proteins were successfully purified via immobilized Ni2+-affinity chromatography. Both positive-charge substitutions (Q574K, Q574R, E581K, E581R) and negative-charge elimination (E581Q) appeared to increase the kinetics of toxin-induced hemolysis while the substitution with a negatively-charged side-chain (Q574E) completely abolished its hemolytic activity. When incorporated into PLBs under symmetrical conditions (1.0 M KCl, pH 7.4), all five mutant toxins with the increased hemolytic activity produced clearly-resolved single channels with higher open probability and longer lifetime than the wild-type toxin, albeit with a half decrease in their maximum conductance. Molecular dynamics simulations for 50 ns of a trimeric CyaA-Hly pore model comprising three α2-loop-α3 transmembrane hairpins revealed a significant role of the positive charge at both target positions in the structural stability and enlarged diameter of the simulated pore. Altogether, our present data have disclosed functional contributions of positively-charged side-chains substituted at positions Gln574 and Glu581 in the pore-lining α3 to the enhanced hemolytic activity and ion-channel opening of CyaA-Hly that actually mimics the highly-active RTX (repeat-in-toxin) cytolysins. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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Review

Jump to: Editorial, Research

22 pages, 2847 KiB  
Review
Bioengineering of Bordetella pertussis Adenylate Cyclase Toxin for Antigen-Delivery and Immunotherapy
by Alexandre Chenal and Daniel Ladant
Toxins 2018, 10(7), 302; https://doi.org/10.3390/toxins10070302 - 20 Jul 2018
Cited by 19 | Viewed by 7837
Abstract
The adenylate cyclase toxin (CyaA) is one of the major virulence factors of Bordetella pertussis, the causative agent of whooping cough. CyaA is able to invade eukaryotic cells where, upon activation by endogenous calmodulin, it synthesizes massive amounts of cAMP that alters [...] Read more.
The adenylate cyclase toxin (CyaA) is one of the major virulence factors of Bordetella pertussis, the causative agent of whooping cough. CyaA is able to invade eukaryotic cells where, upon activation by endogenous calmodulin, it synthesizes massive amounts of cAMP that alters cellular physiology. The CyaA toxin is a 1706 residues-long bifunctional protein: the catalytic domain is located in the 400 amino-proximal residues, whereas the carboxy-terminal 1306 residues are implicated in toxin binding to the cellular receptor, the αMβ2 (CD11b/CD18) integrin, and subsequently in the translocation of the catalytic domain across the cytoplasmic membrane of the target cells. Indeed, this protein is endowed with the unique capability of delivering its N-terminal catalytic domain directly across the plasma membrane of eukaryotic target cells. These properties have been exploited to engineer the CyaA toxin as a potent non-replicating vector able to deliver antigens into antigen presenting cells and elicit specific cell-mediated immune responses. Antigens of interest can be inserted into the CyaA protein to yield recombinant molecules that are targeted in vivo to dendritic cells, where the antigens are processed and presented by the major class I and class II histocompatibility complexes (MHC-I and II). CyaA turned out to be a remarkably effective and versatile vaccine vector capable of inducing all the components of the immune response (T-CD4, T-CD8, and antibody). In this chapter, we summarize the basic knowledge on the adenylate cyclase toxin and then describe the application of CyaA in vaccinology, including some recent results of clinical trials of immunotherapy using a recombinant CyaA vaccine. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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2446 KiB  
Review
Structure–Function Relationships Underlying the Capacity of Bordetella Adenylate Cyclase Toxin to Disarm Host Phagocytes
by Jakub Novak, Ondrej Cerny, Adriana Osickova, Irena Linhartova, Jiri Masin, Ladislav Bumba, Peter Sebo and Radim Osicka
Toxins 2017, 9(10), 300; https://doi.org/10.3390/toxins9100300 - 24 Sep 2017
Cited by 44 | Viewed by 8517
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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1638 KiB  
Review
Understanding the Mechanism of Translocation of Adenylate Cyclase Toxin across Biological Membranes
by Helena Ostolaza, César Martín, David González-Bullón, Kepa B. Uribe and Asier Etxaniz
Toxins 2017, 9(10), 295; https://doi.org/10.3390/toxins9100295 - 21 Sep 2017
Cited by 10 | Viewed by 9592
Abstract
Adenylate cyclase toxin (ACT) is one of the principal virulence factors secreted by the whooping cough causative bacterium Bordetella pertussis, and it has a critical role in colonization of the respiratory tract and establishment of the disease. ACT targets phagocytes via binding [...] Read more.
Adenylate cyclase toxin (ACT) is one of the principal virulence factors secreted by the whooping cough causative bacterium Bordetella pertussis, and it has a critical role in colonization of the respiratory tract and establishment of the disease. ACT targets phagocytes via binding to the CD11b/CD18 integrin and delivers its N-terminal adenylate cyclase (AC) domain directly to the cell cytosol, where it catalyzes unregulated conversion of cytosolic ATP into cAMP upon activation by binding to cellular calmodulin. High cAMP levels disrupt bactericidal functions of the immune cells, ultimately leading to cell death. In spite of its relevance in the ACT biology, the mechanism by which its ≈400 amino acid-long AC domain is transported through the target plasma membrane, and is released into the target cytosol, remains enigmatic. This article is devoted to refresh our knowledge on the mechanism of AC translocation across biological membranes. Two models, the so-called “two-step model” and the recently-proposed “toroidal pore model”, will be considered. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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2837 KiB  
Review
Invasion of Dendritic Cells, Macrophages and Neutrophils by the Bordetella Adenylate Cyclase Toxin: A Subversive Move to Fool Host Immunity
by Giorgio Fedele, Ilaria Schiavoni, Irena Adkins, Nela Klimova and Peter Sebo
Toxins 2017, 9(10), 293; https://doi.org/10.3390/toxins9100293 - 21 Sep 2017
Cited by 36 | Viewed by 11349
Abstract
Adenylate cyclase toxin (CyaA) is released in the course of B. pertussis infection in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense. CD11b-expressing dendritic cells (DC), macrophages and neutrophils are professional phagocytes and key players [...] Read more.
Adenylate cyclase toxin (CyaA) is released in the course of B. pertussis infection in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense. CD11b-expressing dendritic cells (DC), macrophages and neutrophils are professional phagocytes and key players of the innate immune system that provide a first line of defense against invading pathogens. Recent findings revealed the capacity of B. pertussis CyaA to intoxicate DC with high concentrations of 3′,5′-cyclic adenosine monophosphate (cAMP), which ultimately skews the host immune response towards the expansion of Th17 cells and regulatory T cells. CyaA-induced cAMP signaling swiftly incapacitates opsonophagocytosis, oxidative burst and NO-mediated killing of bacteria by neutrophils and macrophages. The subversion of host immune responses by CyaA after delivery into DC, macrophages and neutrophils is the subject of this review. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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941 KiB  
Review
Block V RTX Domain of Adenylate Cyclase from Bordetella pertussis: A Conformationally Dynamic Scaffold for Protein Engineering Applications
by Beyza Bulutoglu and Scott Banta
Toxins 2017, 9(9), 289; https://doi.org/10.3390/toxins9090289 - 17 Sep 2017
Cited by 8 | Viewed by 5772
Abstract
The isolated Block V repeats-in-toxin (RTX) peptide domain of adenylate cyclase (CyaA) from Bordetella pertussis reversibly folds into a β-roll secondary structure upon calcium binding. In this review, we discuss how the conformationally dynamic nature of the peptide is being engineered and employed [...] Read more.
The isolated Block V repeats-in-toxin (RTX) peptide domain of adenylate cyclase (CyaA) from Bordetella pertussis reversibly folds into a β-roll secondary structure upon calcium binding. In this review, we discuss how the conformationally dynamic nature of the peptide is being engineered and employed as a switching mechanism to mediate different protein functions and protein-protein interactions. The peptide has been used as a scaffold for diverse applications including: a precipitation tag for bioseparations, a cross-linking domain for protein hydrogel formation and as an alternative scaffold for biomolecular recognition applications. Proteins and peptides such as the RTX domains that exhibit natural stimulus-responsive behavior are valuable building blocks for emerging synthetic biology applications. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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275 KiB  
Review
Bordetella Adenylate Cyclase-Hemolysin Toxins
by Nicole Guiso
Toxins 2017, 9(9), 277; https://doi.org/10.3390/toxins9090277 - 11 Sep 2017
Cited by 31 | Viewed by 5203
Abstract
Adenylate cyclase-hemolysin toxin is secreted and produced by three classical species of the genus Bordetella: Bordetella pertussis, B. parapertussis and B. bronchiseptica. This toxin has several properties such as: (i) adenylate cyclase activity, enhanced after interaction with the eukaryotic protein, [...] Read more.
Adenylate cyclase-hemolysin toxin is secreted and produced by three classical species of the genus Bordetella: Bordetella pertussis, B. parapertussis and B. bronchiseptica. This toxin has several properties such as: (i) adenylate cyclase activity, enhanced after interaction with the eukaryotic protein, calmodulin; (ii) a pore-forming activity; (iii) an invasive activity. It plays an important role in the pathogenesis of these Bordetella species responsible for whooping cough in humans or persistent respiratory infections in mammals, by modulating host immune responses. In contrast with other Bordetella toxins or adhesins, lack of (or very low polymorphism) is observed in the structural gene encoding this toxin, supporting its importance as well as a potential role as a vaccine antigen against whooping cough. In this article, an overview of the investigations undertaken on this toxin is presented. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
6107 KiB  
Review
Molecular Modeling of the Catalytic Domain of CyaA Deepened the Knowledge of Its Functional Dynamics
by Thérèse E Malliavin
Toxins 2017, 9(7), 199; https://doi.org/10.3390/toxins9070199 - 26 Jun 2017
Cited by 4 | Viewed by 3814
Abstract
Although CyaA has been studied for over three decades and revealed itself to be a very good prototype for developing various biotechnological applications, only a little is known about its functional dynamics and about the conformational landscape of this protein. Molecular dynamics simulations [...] Read more.
Although CyaA has been studied for over three decades and revealed itself to be a very good prototype for developing various biotechnological applications, only a little is known about its functional dynamics and about the conformational landscape of this protein. Molecular dynamics simulations helped to clarify the view on these points in the following way. First, the model of interaction between AC and calmodulin (CaM) has evolved from an interaction centered on the surface between C-CaM hydrophobic patch and the α helix H of AC, to a more balanced view, in which the C-terminal tail of AC along with the C-CaM Calcium loops play an important role. This role has been confirmed by the reduction of the affinity of AC for calmodulin in the presence of R338, D360 and N347 mutations. In addition, enhanced sampling studies have permitted to propose a representation of the conformational space for the isolated AC. It remains to refine this representation using structural low resolution information measured on the inactive state of AC. Finally, due to a virtual screening study on another adenyl cyclase from Bacillus anthracis, weak inhibitors of AC have been discovered. Full article
(This article belongs to the Special Issue Adenylate Cyclase (CyaA) Toxin)
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