Pertussis toxin (PT) is a protein-based AB5-type exotoxin produced by the bacterium Bordetella pertussis,[1] which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection.[2] Research suggests PT may have a therapeutic role in treating a number of common human ailments including hypertension,[3] viral inhibition,[4] and autoimmune inhibition.[5]
Structure
PT is an exotoxin with six subunits (named S1 through S5—each complex contains two copies of S4).[6][7] The subunits are arranged in a A-B structure: the A component is enzymatically active and is formed from the S1 subunit, while the B component is the receptor-binding portion and is made up of subunits S2–S5.[7] The subunits are encoded by ptx genes encoded on a large PT operon that also includes additional genes which encode Ptl proteins: Together these proteins form the PT secretion complex.[8]
Mechanism of pathogenesis
PT is released from B. pertussis in an inactive form. Following PT binding to a cell membrane receptor, it is taken up in an endosome, after which it undergoes retrograde transport to the trans-Golgi network and endoplasmic reticulum[9]. At some point during this transport, the A subunit (or protomer) becomes activated, perhaps through the action of glutathione and ATP.[10] PT catalyzes the ADP-ribosylation of the α subunits of the heterotrimeric G proteins Gi, Go, and Gt. This prevents the G proteins from interacting with G protein-coupled receptors on the cell membrane, thus interfering with intracellular communication.[11] The Gi subunits remain locked in their GDP-bound, inactive state, thus unable to repress acadenyl cyclase activity, leading to increased cellular concentrations of cAMP.
Increased intracellular cAMP affects normal biological signalling and is responsible for the neurogenic disorder that culminates in the paroxysmal, characteristic whooping cough.
The toxin causes several systemic effects, among which is an increased release of insulin, causing hypoglycemia.
References
- ^ Ryan KJ; Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.
- ^ Carbonetti NH, Artamonova GV, Mays RM, Worthington ZE (November 2003). "Pertussis toxin plays an early role in respiratory tract colonization by Bordetella pertussis". Infect. Immun. 71 (11): 6358–66. PMID 14573656. PMC 219603. http://iai.asm.org/cgi/pmidlookup?view=long&pmid=14573656.
- ^ Kost C, Herzer W, Li P, Jackson E (1999). "Pertussis toxin-sensitive G-proteins and regulation of blood pressure in the spontaneously hypertensive rat". Clin Exp Pharmacol Physiol 26 (5-6): 449–55. doi:. PMID 10386237.
- ^ Alfano M, Pushkarsky T, Poli G, Bukrinsky M (2000). "The B-oligomer of pertussis toxin inhibits human immunodeficiency virus type 1 replication at multiple stages". J Virol 74 (18): 8767–70. doi:. PMID 10954581.
- ^ Bagley K, Abdelwahab S, Tuskan R, Fouts T, Lewis G (2002). "Pertussis toxin and the adenylate cyclase toxin from Bordetella pertussis activate human monocyte-derived dendritic cells and dominantly inhibit cytokine production through a cAMP-dependent pathway". J Leukoc Biol 72 (5): 962–9. PMID 12429718.
- ^ Kaslow HR, Burns DL (June 1992). "Pertussis toxin and target eukaryotic cells: binding, entry, and activation". FASEB J. 6 (9): 2684–90. PMID 1612292. http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=1612292.
- ^ a b Locht C, Antoine R (1995). "A proposed mechanism of ADP-ribosylation catalyzed by the pertussis toxin S1 subunit". Biochimie 77 (5): 333–40. doi:. PMID 8527486.
- ^ Weiss A, Johnson F, Burns D (1993). "Molecular characterization of an operon required for pertussis toxin secretion". Proc Natl Acad Sci U S A 90 (7): 2970–4. doi:. PMID 8464913.
- ^ Plaut RD, Carbonetti NH (May 2008). "Retrograde transport of pertussis toxin in the mammalian cell". Cell. Microbiol. 10 (5): 1130–9. doi:. PMID 18201245. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1462-5814&date=2008&volume=10&issue=5&spage=1130.
- ^ Finger H, von Koenig CHW (1996). "Bordetella". in Barron S, et al.. Barron's Medical Microbiology (4th ed.). Univ of Texas Medical Branch. ISBN 0-9631172-1-1. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.1706.
- ^ Burns D (1988). "Subunit structure and enzymic activity of pertussis toxin". Microbiol Sci 5 (9): 285–7. PMID 2908558.
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