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Identified Virulence Factors of Bordetella : Toxin

Cya (Invasive Adenylate cyclase /haemolysin)  

Related genes: cyaA; cyaB; cyaC; cyaD; cyaE;
Keywords: Toxin; Adenylate cyclase; RTX toxin;
Originally identified as a hemolysin because it will lyse red blood cells
Secreted by type I pathway and secretion requires CyaB, D, E proteins
Structure features:
1706 residues-long protein, calmodulin-activated adenylate cyclase catalytic activity is located within the N-terminal 400 amino acids. The remaining 1306aa C-terminal cell binding domain, homologous to the Repeats-in-Toxin (RTX) family of calcium-binding, pore-forming bacterial protein toxins, mediates delivery of the catalytic domain into the cytoplasm of eukaryotic cells. The latter consists itself of three functional domains typical for RTX hemolysins. It harbors, respectively, (i) a hydrophobic pore-forming domain, (ii) a segment recognized by the protein acyltransferase CyaC, activating proCyaA by covalent post-translational palmitoylation at ε-amino groups of Lys860 and Lys983, and (iii) an assembly of five blocks of the characteristic glycine and aspartate-rich nonapeptide RTX repeats that form numerous calcium binding sites.
Adenylate cyclase toxin mediated virulence in Bordetella spp. (From: Melvin JA, et al., 2014. Bordetella pertussis pathogenesis: current and future challenges. Nat Rev Microbiol 12(4):274-88.)

Bifunctional toxin harboring both adenylate cyclase and hemolytic activities
Functions primarily as an anti-inflammatory factor
Binds to αMβ2 integrin (CD11b/CD18, Mac-1, or CR3), activated by calmodulin and catalyzes the production of intracellular cAMP from ATP. This uncontrolled cAMP concentration leads to paralysis of the killing functions in phagocytic and immune effector cells
Cotter PA, Miller JF, 2001. Bordetella In Groisman EA (ed.), Principles of Bacterial pathogenesis. Academic Press. San Diego, Calif. pp. 619-674.
Khelef N, et al., 1992. Both adenylate cyclase and hemolytic activities are required by Bordetella pertussis to initiate infection. Microb. Pathog. 12(3):227-235.
Sakamoto H, et al., 1992. Bordetella pertussis adenylate cyclase toxin. Structural and functional independence of the catalytic and hemolytic activities. J. Biol. Chem. 267(19):13598-13602.
Barry EM, et al., 1991. Bordetella pertussis adenylate cyclase toxin and hemolytic activities require a second gene, cyaC, for activation. J. Bacteriol. 173(2):720-726.
Glaser P, et al., 1988. Secretion of cyclolysin, the calmodulin-sensitive adenylate cyclase-haemolysin bifunctional protein of Bordetella pertussis. EMBO J. 7(12):3997-4004.
Hackett M, et al., 1994. Internal lysine palmitoylation in adenylate cyclase toxin from Bordetella pertussis. Science 266(5184):433-435.
Smith AM, et al., 2001. The virulence factors of Bordetella pertussis: a matter of control. FEMS Microbiol. Rev. 25(3):309-333.
Gallay J, et al., 2004. Insight into the activation mechanism of Bordetella pertussis adenylate cyclase by calmodulin using fluorescence spectroscopy. Eur. J. Biochem. 271(4):821-833.
Martin C, et al., 2004. Membrane restructuring by Bordetella pertussis adenylate cyclase toxin, a member of the RTX toxin family. J. Bacteriol. 186(12):3760-3765.
Bumba L, et al., 2010. Bordetella adenylate cyclase toxin mobilizes its beta2 integrin receptor into lipid rafts to accomplish translocation across target cell membrane in two steps. PLoS Pathog. 6(5):e1000901.

Dnt (Dermonecrotic toxin)  

Related genes: dnt;
Keywords: Toxin; Intracellular toxin; Deamidase; A-B type;
Homology to a family of toxins including the cytotoxic necrotising factor (CNF) of E.coli, botulinum C3 toxin and Pasteurella multocida toxin
Structure features:
DNT is an A-B type toxin composed of N-terminal receptor-binding (B) domain and a C-terminal enzymatically active (A) domain
Dermonecrosis-inducing toxin stimulates the assembly of actin stress fibers and focal adhesions by deamidating or polyaminating small GTPase Rho
The C-terminal part of Dnt deamidates a glutamine residue (Glu63) of Rho protein. Deamidation and transglutamination induced by Dnt blocked intrinsic and Rho-GTPase-activating protein-stimulated GTPase activity of Rho protein, which results in tyrosine phosphorylation of focal adhesion kinase (p125fak) and paxillin. p125fak and paxillin are involved in embryonic development and cell locomotion
Horiguchi Y, et al., 1997. Bordetella bronchiseptica dermonecrotizing toxin induces reorganization of actin stress fibers through deamidation of Gln-63 of the GTP-binding protein Rho. Proc. Natl. Acad. Sci. USA. 94(21):11623-11626.
Schmidt G, et al., 1999. Identification of the C-terminal part of Bordetella dermonecrotic toxin as a transglutaminase for rho GTPases. J. Biol. Chem. 274(45):31875-31881.
Masuda M, et al., 2000. Activation of rho through a cross-link with polyamines catalyzed by Bordetella dermonecrotizing toxin. EMBO J. 19(4):521-530.
Horiguchi Y, 2001. Escherichia coli cytotoxic necrotizing factors and Bordetella dermonecrotic toxin: the dermonecrosis-inducing toxins activating Rho small GTPases. Toxicon 39(11):1619-1627.
Schmidt G, et al., 2001. Lysine and polyamines are substrates for transglutamination of Rho by the Bordetella dermonecrotic toxin. Infect. Immun. 69(12):7663-7670.
Masuda M, et al., 2002. In vivo modifications of small GTPase Rac and Cdc42 by Bordetella dermonecrotic toxin. Infect. Immun. 70(2):998-1001.
Matsuzawa T, et al., 2002. Identification of a receptor-binding domain of Bordetella dermonecrotic toxin. Infect. Immun. 70(7):3427-3432.
Fukui-Miyazaki A, et al., 2011. Bordetella dermonecrotic toxin binds to target cells via the N-terminal 30 amino acids. Microbiol. Immunol. 55(3):154-159.

Ptx (Pertussis toxin)  

Related genes: ptlA; ptlB; ptlC; ptlD; ptlE; ptlF; ptlG; ptlH; ptlI; ptxA; ptxB; ptxC; ptxD; ptxE;
Keywords: Toxin; Intracellular toxin; ADP-ribosyltransferase; A-B type; Adherence; Type IV secretory protein;
Only B. pertussis producs Ptx in vitro, ptx-ptl loci is present in B. parapertussis and B. bronchiseptica but these genes may be tightly regulated and therefore are expressed only in vivo, while the recent mutations in the promoter region increased the transcription of the gene in B. pertusis
Secreted by type IV secretion system: Ptl
Structure features:
A member of the A-B bacterial toxin superfamily, Ptx is a hexameric protein comprising five distinct subunits, designated S1-S5. S2, S3, S4 and S5 comprise the B oligomer, responsible for binding the toxin to the cell surface. Each subunit is translated separately with an amino-terminal signal sequence which is cleaved during transport to the periplasm. Secretion across the outer membrane requires a specialized transport apparatus composed of nine Ptl (pertussis toxin liberation) proteins
PDB code: 1PRT
ptx/ptl locus and Ptl secretion machinery. (From: Locht C, et al., 2011. The ins and outs of pertussis toxin. FEBS J. 278(23):4668-4682.)

Intracellular trafficking of Ptx.

Attachment of B. pertussis to ciliated respiratory cells
Important immunogen
Activates cyclic adenosine phosphate (cAMP), histamine sensitising factor (HSF), lymphocytosis promoting factor (LPF), islet-activating protein (IAP), interferes with leucocyte function, haemolytic
Although specific receptors for Ptx have not been identified, many cell surface sialoglycoproteins may serve as PTX receptors. The toxin can also bind to glycoproteins, such as haptoglobin and fetuin, which have served as model proteins for PTX receptors.
The A protomer, consisting of the enzymatically active S1 subunit
The B oligomer, formed by the remaining S2-S5 subunits. The B oligomer binds to eukaryotic cell membranes and dramatically increases the efficiency with which the S1 subunit gains entry into host cells
ADP-ribosylates the α-subunits Gi, Go and Ggust. This modification causes the silencing of the inhibitory input and induces the indirect activation of downstream effectors
S2 and S3 function as adhesins, S2 binds specifically to a glycolipid called lactosylceramide, which is found primarily on the ciliated epithelial cells. S3 binds to a glycoprotein found mainly on phagocytic cells
Cotter PA, Miller JF, 2001. Bordetella In Groisman EA (ed.), Principles of Bacterial pathogenesis. Academic Press. San Diego, Calif. pp. 619-674.
Saukkonen K, et al., 1992. Pertussis toxin has eukaryotic-like carbohydrate recognition domains. Proc. Natl. Acad. Sci. USA. 89(1):118-122.
Nencioni L, et al., 1991. Properties of the B oligomer of pertussis toxin. Infect. Immun. 59(12):4732-4734.
Witvliet MH, et al., 1989. Binding of pertussis toxin to eucaryotic cells and glycoproteins. Infect. Immun. 57(11):3324-3330.
Katada T, et al., 1983. The A protomer of islet-activating protein, pertussis toxin, as an active peptide catalyzing ADP-ribosylation of a membrane protein. Arch Biochem. Biophys. 224(1):290-298.
Weiss AA, et al., 1993. Molecular characterization of an operon required for pertussis toxin secretion. Proc. Natl. Acad. Sci. USA. 90(7):2970-2974.
Smith AM, et al., 2001. The virulence factors of Bordetella pertussis: a matter of control. FEMS Microbiol. Rev. 25(3):309-333.
Locht C, et al., 2011. The ins and outs of pertussis toxin. FEBS J. 278(23):4668-4682.

TCT (Tracheal cytotoxin)  

Keywords: Toxin; Cytotoxin;
A classic bacterial exotoxin since it is not composed of protein. The tracheal cytotoxin is a cell wall breakdown product, a peptidoglycan fragment
Structure features:
A disaccharide-tetrapeptide monomer of peptidoglycan, its structure is N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-(L)-alanyl-γ-(D)-glultamyl-mesodiaminopimelyl-(D)-alanine
Peptidoglycan and tracheal cytotoxin structure. (From: Cloud-Hansen KA, et al., 2006. Breaching the great wall: peptidoglycan and microbial interactions. Nat Rev Microbiol 4(9):710-6.)

Causing loss of ciliated cells, cell blebbing and mitochondrial damage. The destruction of cilia and ciliated epithelial cells by TCT causes ciliostasis and forces the infected individual to cough relentlessly in order to remove mucus
Inducing host cells to produce IL-1α, this activates host cell nitric oxide synthase leading to high levels of nitric oxide radicals. The nitric oxide acts by destroying iron-dependent enzymes, eventually inhibiting mitochondrial function and DNA synthesis in nearby host cells
Cotter PA, Miller JF, 2001. Bordetella In Groisman EA (ed.), Principles of Bacterial pathogenesis. Academic Press. San Diego, Calif. pp. 619-674.
Luker KE, et al., 1995. Tracheal cytotoxin structural requirements for respiratory epithelial damage in pertussis. Mol. Microbiol. 16(4):733-743.
Luker KE, et al., 1993. Bordetella pertussis tracheal cytotoxin and other muramyl peptides: distinct structure-activity relationships for respiratory epithelial cytopathology. Proc. Natl. Acad. Sci. USA. 90(6):2365-2369.
Flak TA, Goldman WE, 1999. Signalling and cellular specificity of airway nitric oxide production in pertussis. Cell Microbiol. 1(1):51-60.
Smith AM, et al., 2001. The virulence factors of Bordetella pertussis: a matter of control. FEMS Microbiol. Rev. 25(3):309-333.
Magalhaes JG, et al., 2005. Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin. EMBO Rep. 6(12):1201-1207.

RTX toxin
The term RTX (repeat in toxin) derives from the characteristic amino acid repeats (a tandem duplication of glycine-rich nine amino acids (XXGGXGXDX; X=any amino acid), responsible for Calcium binding) present towards the C-terminus of all members of this toxin family

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