Pertussis toxin (PT) is a protein-basedAB5-typeexotoxin produced by thebacteriumBordetella pertussis,[2] which causeswhooping cough. PT is involved in the colonization of therespiratory tract and the establishment of infection.[3] Research suggests PT may have a therapeutic role in treating a number of common human ailments, including hypertension,[4] viral infection,[5] and autoimmunity.[6][7][8]
PT clearly plays a central role in thepathogenesis ofpertussis although this was discovered only in the early 1980s. The appearance of pertussis is quite recent, compared with other epidemic infectious diseases. The earliest mention of pertussis, or whooping cough, is of an outbreak in Paris in 1414. This was published in Moulton's The Mirror of Health, in 1640. Another epidemic of pertussis took place in Paris in 1578 and was described by a contemporary observer,Guillaume de Baillou. Pertussis was well known throughout Europe by the middle of the 18th century. Jules Bordet and Octave Gengou described in 1900 the finding of a new "ovoid bacillus" in the sputum of a 6-month-old infant with whooping cough. They were also the first to cultivateBordetella pertussis at thePasteur Institute in Brussels in 1906.[9]
One difference between the different species ofBordetella is thatB. pertussis produces PT and the other species do not.Bordetella parapertussis shows the most similarity toB. pertussis and was therefore used for research determining the role of PT in causing the typical symptoms of whooping cough. Rat studies showed the development of paroxysmal coughing, a characteristic for whooping cough, occurred in rats infected withB. pertussis. Rats infected withB. parapertussis or a PT-deficient mutant ofB. pertussis did not show this symptom; neither of these two strains produced PT.[10]
A large group of bacterialexotoxins are referred to as "A/B toxins", in essence because they are formed from two subunits.[11] The "A" subunit possesses enzyme activity and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit.[11] Pertussis toxin is an exotoxin with six subunits (namedS1 throughS5—each complex contains two copies ofS4).[12][13] The subunits are arranged inA-B structure: theA component isenzymatically active and is formed from the S1 subunit, while theB component is thereceptor-binding portion and is made up of subunits S2–S5.[13] The subunits are encoded byptx genes encoded on a large PToperon that also includes additional genes that encode Ptl proteins. Together, these proteins form the PT secretion complex.[14]
PT is released fromB. pertussis in an inactive form. Following PT binding to acell membrane receptor, it is taken up in anendosome, after which it undergoes retrograde transport to thetrans-Golgi network andendoplasmic reticulum.[15] At some point during this transport, the A subunit (or protomer) becomes activated, perhaps through the action ofglutathione andATP.[12][16] PT catalyzes theADP-ribosylation of theαi subunits of theheterotrimeric G protein. This prevents the G proteins from interacting withG protein-coupled receptors on thecell membrane, thus interfering with intracellular communication.[17] The Gi subunits remain locked in their GDP-bound, inactive state, thus unable to inhibit adenylate cyclase activity, leading to increased cellular concentrations of cAMP.
Increased intracellular cAMP affects normal biological signaling. The toxin causes several systemic effects, among which is an increased release ofinsulin, causinghypoglycemia. Whether the effects of pertussis toxin are responsible for the paroxysmal cough remains unknown.[18]
As a result of this unique mechanism, PT has also become widely used as a biochemical tool to ADP-ribosylate GTP-binding proteins in the study of signal transduction.[1] It has also become an essential component of new acellular vaccines.[1]
PT has been shown to affect the innate immune response. It inhibits the early recruitment ofneutrophils andmacrophages, and interferes with earlychemokine production and neutrophilchemotaxis.[19] Chemokines are signaling molecules produced by infected cells and attract neutrophils and macrophages. Neutrophil chemotaxis is thought to be disrupted by inhibiting G-protein-coupled chemokine receptors by the ADP-ribosylation of Gi proteins.[20]
Due to the disrupted signaling pathways, synthesis of chemokines will be affected. This will prevent the infected cell from producing them and thereby inhibiting recruitment of neutrophils. Under normal circumstances, alveolar macrophages and other lung cells produce a variety of chemokines. PT has been found to inhibit the early transcription of keratinocyte-derived chemokine, macrophage inflammatory protein 2 andLPS-induced CXC chemokine.[20] Eventually, PT causeslymphocytosis, one of the systemic manifestations of whooping cough.[21]
PT, a decisive virulence determinant ofB. pertussis, is able to cross the blood–brain barrier by increasing its permeability.[22] As a result, PT can cause severe neurological complications; however, recently it has been found that the medicinal usage ofPertussis toxin can promote the development of regulatory T cells and prevent central nervous system autoimmune disease, such as multiple sclerosis.[23]
PT is known to dissociate into two parts in the endoplasmic reticulum (ER): the enzymatically active A subunit (S1) and the cell-binding B subunit. The two subunits are separated by proteolic cleavage. The B subunit will undergo ubiquitin-dependent degradation by the 26Sproteasome. However, the A subunit lackslysine residues, which are essential forubiquitin-dependent degradation. Therefore, PT subunit A will not be metabolized like most other proteins.[24]
PT is heat-stable and protease-resistant, but once the A and B are separated, these properties change. The B subunit will stay heat-stable at temperatures up to 60 °C, but it is susceptible to protein degradation. PT subunit A, on the other hand, is less susceptible to ubiquitin-dependent degradation, but is unstable at temperature of 37 °C. This facilitates unfolding of the protein in the ER and tricks the cell into transporting the A subunit to the cytosol, where normally unfolded proteins will be marked for degradation. So, the unfolded conformation will stimulate theERAD-mediated translocation of PT A into the cytosol. Once in the cytosol, it can bind to NAD and form a stable, folded protein again. Being thermally unstable is also the Achilles heel of PT subunit A. As always, there is an equilibrium between the folded and unfolded states. When the protein is unfolded, it is susceptible to degradation by the 20S proteasome, which can degrade only unfolded proteins.[24]
ptxP is the pertussis toxin's promoter gene. There is a well documented emergence and global spread ofptxP3 strains evolving from and replacing the nativeptxP1 strains,[25] associated with an increased production of the toxin, and thus an increased virulence.[26] Such spread has been documented in multiple countries, and sometimes but not always linked to the resurgence of pertussis in the end of the 20th century. Countries with a documented spread ofptxP3 include Australia,[26][27] Denmark,[28] Finland,[29] Iran,[30] Italy,[31] Japan,[32] the Netherlands,[33] and Sweden.[34]
^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:10.1046/j.1440-1681.1999.03058.x.PMID10386237.S2CID12902466.
^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.doi:10.1189/jlb.72.5.962.PMID12429718.S2CID16457655.
^abLocht C, Antoine R (1995). "A proposed mechanism of ADP-ribosylation catalyzed by the pertussis toxin S1 subunit".Biochimie.77 (5):333–40.doi:10.1016/0300-9084(96)88143-0.PMID8527486.
^Finger H, von Koenig CH (1996)."Bordetella". In Barron S, et al. (eds.).Barron's Medical Microbiology (4th ed.). Univ of Texas Medical Branch.ISBN0-9631172-1-1.PMID21413270.
^Burns D (1988). "Subunit structure and enzymic activity of pertussis toxin".Microbiol Sci.5 (9):285–7.PMID2908558.
