|Flagellated B. bronchiseptica|
Flagellated B. bronchiseptica
Bordetella is a genus of small (0.2 - 0.7 µm), Gram-negative coccobacilli of the phylum proteobacteria. Bordetella species, with the exception of B. petrii, are obligate aerobes as well as highly fastidious, or difficult to culture. Three species are human pathogens (B. pertussis, B. parapertussis, B. bronchiseptica); one of these (B. bronchiseptica) is also motile.
B. pertussis and occasionally B. parapertussis cause pertussis or whooping cough in humans, and some B. parapertussis strains can colonise sheep. B. bronchiseptica rarely infects healthy humans though disease in immunocompromised patients has been reported. B. bronchiseptica causes several diseases in other mammals, including kennel cough and atrophic rhinitis in dogs and pigs, respectively. Other members of the genus cause similar diseases in other mammals, and in birds (B. hinzii, B. avium).
The Bordetella genus is named after Jules Bordet.
Pathogenesis of Bordetella infections
The most thoroughly studied of the Bordetella species are B. bronchiseptica, B. pertussis and B. parapertussis and the pathogenesis of respiratory disease caused by these bacteria has been reviewed. Transmission occurs by direct contact, or via respiratory aerosol droplets, or fomites. Bacteria initially adhere to ciliated epithelial cells in the nasopharynx and this interaction with epithelial cells is mediated by a series of protein adhesins. These include filamentous haemaglutinin, pertactin, fimbriae, and pertussis toxin (though expression of pertussis toxin is unique to B. pertussis). As well as assisting in adherence to epithelial cells, some of these are also involved in attachment to immune effector cells.
The initial catarrhal phase of infection produces symptoms similar to those of the common cold and during this period, large numbers of bacteria can be recovered from the pharynx. Thereafter the bacteria proliferate and spread further into the respiratory tract, where the secretion of toxins causes ciliostasis and facilitates the entry of bacteria to tracheal/bronchial ciliated cells. One of the first toxins to be expressed is tracheal cytotoxin which is a disaccharide-tetrapeptide derived from peptidoglycan. Unlike most other Bordetella toxins, tracheal cytotoxin is expressed constitutively, being a normal product of the breakdown of the bacterial cell wall. Other bacteria recycle this molecule back into the cytoplasm, but in Bordetella and Neisseria gonorrhoeae it is released into the environment. Tracheal cytotoxin itself is able to reproduce paralysis of the ciliary escalator, inhibition of DNA synthesis in epithelial cells and ultimately killing of the same. One of the most important of the regulated toxins is adenylate cyclase toxin, which aids in the evasion of innate immunity. The toxin is delivered to phagocytic immune cells upon contact. Immune cell functions are then inhibited in part by the resulting accumulation of cyclic AMP. Recently discovered activities of adenylate cyclase toxin, including transmembrane pore formation and stimulation of calcium influx, may also contribute to the intoxication of phagocytes.
Regulation of virulence factor expression in Bordetella
The expression of many Bordetella adhesins and toxins is controlled by the two-component regulatory system BvgAS. Much of what is known about this regulatory system is based on work with B. bronchiseptica but BvgAS is present in B. pertussis, B. parapertussis and B. bronchiseptica and is responsible for phase variation or phenotypic modulation.
BvgS is a plasma membrane-bound sensor kinase which responds to stimulation by phosphorylating a cytoplasmic helix-turn-helix-containing protein, BvgA. When phosphorylated, BvgA has increased affinity for specific binding sites in Bvg-activated promoter sequences and is able to promote transcription in in vitro assays.
Most of the toxins and adhesins under BvgAS control are expressed under Bvg+ conditions (high BvgA-Pi concentration). But there are also genes expressed solely in the Bvg- state, most notably the flagellin gene flaA. The regulation of Bvg repressed genes is mediated by the product of a 624-bp open reading frame downstream of bvgA, the so-called Bvg-activated repressor protein, BvgR. BvgR binds to a consensus sequence present within the coding sequences of at least some Bvg-repressed genes. Binding of this protein to the consensus sequence represses gene expression by reducing transcription.
It is not known what the physiological signals for BvgS are, but in vitro BvgAS can be inactivated by millimolar concentrations of magnesium sulphate or nicotinic acid, or by reduction of the incubation temperature to ≤ 26°C.
The identification of a specific point mutation in the bvgS gene which locks B. bronchiseptica in an intermediate Bvg phase revealed a class of BvgAS-regulated genes that are exclusively transcribed under intermediate concentrations of BvgA-Pi. This intermediate (Bvgi) phenotype can be reproduced in wild-type B. bronchiseptica by growth of the bacteria in medium containing intermediate concentrations of the BvgAS modulator, nicotinic acid. In these conditions some, but not all of the virulence factors associated with the Bvg+ phase are expressed suggesting that this two component regulatory system can give rise to a continuum of phenotypic states in response to the environment.
- Ryan KJ; Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed. ed.). McGraw Hill. ISBN 0838585299.
- Bauwens J, Spach D, Schacker T, Mustafa M, Bowden R (1992). "Bordetella bronchiseptica pneumonia and bacteremia following bone marrow transplantation". J Clin Microbiol. 30 (9): 2474–5. PMID 1401019.
- Hewlett E (1997). "Pertussis: current concepts of pathogenesis and prevention". Pediatr Infect Dis J. 16 (4 Suppl): S78–84. PMID 9109161.
- Cotter PA, Miller JF (2000). Bordetella in: Principles of Bacterial Pathogenesis (Groisman EA, ed.). Academic Press. pp. pp. 620-85. ISBN 0123042208.
- Mattoo S, Cherry J (2005). "Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies". Clin Microbiol Rev. 18 (2): 326–82. PMID 15831828.
- Gray MC, Donato GM, Jones FR, Kim T, Hewlett EL (2004). "Newly secreted adenylate cyclase toxin is responsible for intoxication of target cells by Bordetella pertussis". Mol. Microbiol. 53 (6): 1709–19. doi:10.1111/j.1365-2958.2004.04227.x. PMID 15341649.
- Hewlett EL, Donato GM, Gray MC (2006). "Macrophage cytotoxicity produced by adenylate cyclase toxin from Bordetella pertussis: more than just making cyclic AMP!". Mol. Microbiol. 59 (2): 447–59. doi:10.1111/j.1365-2958.2005.04958.x. PMID 16390441.
- Fiser R, Masín J, Basler M, Krusek J, Spuláková V, Konopásek I, Sebo P (2007). "Third activity of Bordetella adenylate cyclase (AC) toxin-hemolysin. Membrane translocation of AC domain polypeptide promotes calcium influx into CD11b+ monocytes independently of the catalytic and hemolytic activities". J. Biol. Chem. 282 (5): 2808–20. doi:10.1074/jbc.M609979200. PMID 17148436.
- Uhl M, Miller J (1994). "Autophosphorylation and phosphotransfer in the Bordetella pertussis BvgAS signal transduction cascade". Proc Natl Acad Sci U S A. 91 (3): 1163–7. PMID 8302847.
- Steffen P, Goyard S, Ullmann A (1996). "Phosphorylated BvgA is sufficient for transcriptional activation of virulence-regulated genes in Bordetella pertussis". EMBO J. 15 (1): 102–9. PMID 8598192.
- Akerley B, Monack D, Falkow S, Miller J (1992). "The bvgAS locus negatively controls motility and synthesis of flagella in Bordetella bronchiseptica". J Bacteriol. 174 (3): 980–90. PMID 1370665.
- Merkel T, Stibitz S (1995). "Identification of a locus required for the regulation of bvg-repressed genes in Bordetella pertussis". J Bacteriol. 177 (10): 2727–36. PMID 7751282.
- Beattie D, Mahan M, Mekalanos J (1993). "Repressor binding to a regulatory site in the DNA coding sequence is sufficient to confer transcriptional regulation of the vir-repressed genes (vrg genes) in Bordetella pertussis". J Bacteriol. 175 (2): 519–27. PMID 8419298.
- Cotter P, Miller J (1997). "A mutation in the Bordetella bronchiseptica bvgS gene results in reduced virulence and increased resistance to starvation, and identifies a new class of Bvg-regulated antigens". Mol Microbiol. 24 (4): 671–85. PMID 9194696.
- van den Akker W (1997). "Bordetella bronchiseptica has a BvgAS-controlled cytotoxic effect upon interaction with epithelial cells". FEMS Microbiol Lett. 156 (2): 239–44. PMID 9513272.