Tracheal cytotoxin

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Tracheal cytotoxin 2D.svg
Names
IUPAC name
(2R,6S)-6-[[(4R)-4-[[(2S)-2-[[(2R)-2-[[(1R,2S,3R,4R,5R)-4-acetamido-2-[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6,8-dioxabicyclo[3.2.1]octan-3-yl]oxy]propanoyl]amino]propanoyl]amino]-4-carboxybutanoyl]amino]-2-amino-7-[[(1R)-1-carboxyethyl]amino]-7-oxoheptanoic acid
Other names
  • TCT
  • Tracheal cytotoxin, bordetella pertussis
  • GlcNAc(beta1-4)-MurNAc(1,6-anhydro)-L-Ala-gamma-D-Glu-meso-A2pm-D-Ala
  • GlcNAc-1,6-anhMurNAc-L-Ala-gamma-D-Glu-DAP-D-Ala (physiological form; two fewer protons)
Identifiers
3D model (JSmol)
DrugBank
PubChem CID
  • C[C@@H](C(=O)N[C@H](CCC(=O)N[C@@H](CCC[C@H](C(=O)O)N)C(=O)N[C@H](C)C(=O)O)C(=O)O)NC(=O)[C@@H](C)O[C@@H]1[C@H]([C@@H]2OC[C@H]([C@H]1O[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)NC(=O)C)O2)NC(=O)C
Properties
C37H59N7O20
Molar mass 921.908 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Tracheal cytotoxin (TCT) is a 921 dalton glycopeptide released by Bordetella pertussis , [1] Vibrio fischeri (as a symbiosis chemical), [2] and Neisseria gonorrhoeae (among other peptidoglycan-derived cytotoxins it produces). [3] It is a soluble piece of peptidoglycan (PGN) found in the cell wall of all gram-negative bacteria, [4] but only some bacteria species release TCT due to inability to recycle this piece of anhydromuropeptide. [5]

Contents

History

In 1980, it was discovered that B. pertussis could attach to hamster tracheal epithelial (HTE) cells, and also, that the supernatant from the cultured bacterium could disrupt the cell cycle of uninfected cells. [6] This prompted the scientists W. E. Goldman, D. G. Klapper, and J. B. Baseman to isolate and characterize a novel substance from B. pertussis supernatant. The novel disaccharide tetrapeptide that they had purified showed toxicity for HTE cells and tracheal ring cultures. Subsequently, they named the newly sequestered molecule tracheal cytotoxin (TCT). [7]

Structure

Molecular structure of TCT TCT structure.png
Molecular structure of TCT

TCT is a soluble piece of peptidoglycan (PGN) found in the cell wall of all gram-negative bacteria. [4] Like all PGNs, TCT is composed of a disaccharide and a peptide chain. The IUPAC name for TCT is N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-(L)-alanyl-γ-(D)-glutamyl-mesodiaminopimelyl-(D)-alanine. [8] It is classified as a DAP (diaminopimelic acid)-type PGN due to the third amino group within the chain being a diaminopimelyl peptide.[ citation needed ]

Configuration of TCT within the cell wall of a bacterium TCT within Cell Wall.JPG
Configuration of TCT within the cell wall of a bacterium

The DAP residue is responsible for directly bonding to the D-alanine peptide of another PGN molecule, thus aiding TCT's attachment within the cell wall. [9]

Analogs of TCT. LacAEDapA retains the peptide chain of TCT along with toxicity despite the lack of disaccharide. LacAEaApmA loses the diamino group of TCT along with a significant level of toxicity. TCT Analogs.JPG
Analogs of TCT. LacAEDapA retains the peptide chain of TCT along with toxicity despite the lack of disaccharide. LacAEαApmA loses the diamino group of TCT along with a significant level of toxicity.

The DAP portion of TCT also implies importance in cytopathogenicity as analogs lacking DAP show a significant reduction in toxicity. [10]

Mechanism of pathogenesis

Most Gram-negative bacteria keep TCT within the cell wall by using a PGN-transporter protein known as AmpG. However, B. pertussis is not capable of recycling PGNs via AmpG and thus, TCT escapes into the surrounding environment. [11] [5] Also, TCT appears to be constitutively expressed[ dubious – discuss ] by B. pertussis. [4]

The first murine-model studies using TCT involved treatment of hamster tracheal cells. These experiments alluded to TCT's role in ciliostasis and cellular extrusion of ciliated hamster cells. Also, HTE cells had a markedly reduced level of DNA synthesis post-treatment with TCT.

Illustration showing the effects of TCT on human ciliated epithelial cells. Figure A illustrates normal human epithelial tissue. Figure B illustrates normal human epithelial tissue after incubation with TCT. Notice the damaged and extruded ciliated epithelial cells in Figure B. TCTonEpithelialCells.JPG
Illustration showing the effects of TCT on human ciliated epithelial cells. Figure A illustrates normal human epithelial tissue. Figure B illustrates normal human epithelial tissue after incubation with TCT. Notice the damaged and extruded ciliated epithelial cells in Figure B.

While previous studies using murine models reported evidence of TCT causing ciliostasis, in vitro studies using human tracheal cells have shown that TCT does not affect ciliary beat frequency of living cells, but instead causes damage and eventual extrusion of ciliated cells. [12] In gonorrhea infections, vaginal ciliated epithelial cells have also displayed the same cytopathogenic effects due to TCT recognition. [13] The extensive damage to ciliated epithelial tissue caused by TCT results in major disruption to the ciliary escalator; an important asset of the host's non-specific defenses. This disruption hinders the host's ability to remove mucous and foreign microbes from the epithelial tissue. Paroxysmal cough, e.g. whooping cough, is a direct symptom of said mucous build-up due to ciliated tissue damage.[ citation needed ]

NOD-1 recognition and the presence of Lipooligosaccharide (LOS) are two factors that modulate the effect of TCT. NOD-1 is a pattern recognition receptor that detects peptidoglycan. This receptor reacts weakly to TCT in humans, but robustly in mice. TCT is thought to work synergistically with LOS to mediate an inflammatory response, thus causing damage to ciliated epithelial cells. [14] Notably, the human pathogens (B. pertussis and N. gonorrhea) that produce excess TCT, causing damage to cilia also both produce LOS in their outer membrane.[ citation needed ]

Effect on immune system

TCT has been classified as an adjuvant molecule because of the stimulating effects it has on the immune system. Cellular damage associated with TCT is thought to be a result of increased levels of nitric oxide (NO) secretion by mucosal cells as part of an innate defense response to extracellular lipopolysaccharide (LPS) and TCT. [15] In humans, peptidoglycan recognition proteins, e.g. PGRPIαC, appear to bind with TCT and consequently induce the Tumor Necrosis Factor Receptor (TNFR) pathway. [16] Studies using murine macrophages have shown that TCT encourages cytokine secretion, probably through the NOD1 receptor. [17] As a pleiotropic toxin, TCT also acts as a pyrogen and as a stimulant of slow-wave sleep. [18]

Peptidoglycan recognition protein 4 (PGLYRP4), in mammals (mice), interacts with TCT and reduces damage from pertussis inflammation. [19] This molecule has similar immune-eliciting properties in Drosophila , where a pair of PGRPs perform the recognition. [20]

Related Research Articles

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.

<span class="mw-page-title-main">Pertactin</span> Virulence factor of Bordetella pertussis

In molecular biology, pertactin (PRN) is a highly immunogenic virulence factor of Bordetella pertussis, the bacterium that causes pertussis. Specifically, it is an outer membrane protein that promotes adhesion to tracheal epithelial cells. PRN is purified from Bordetella pertussis and is used for the vaccine production as one of the important components of acellular pertussis vaccine.

<i>Bordetella</i> Genus of bacteria

Bordetella is a genus of small, Gram-negative, coccobacilli bacteria of the phylum Pseudomonadota. Bordetella species, with the exception of B. petrii, are obligate aerobes, as well as highly fastidious, or difficult to culture. All species can infect humans. The first three species to be described ; are sometimes referred to as the 'classical species'. Two of these are also motile.

Adhesins are cell-surface components or appendages of bacteria that facilitate adhesion or adherence to other cells or to surfaces, usually in the host they are infecting or living in. Adhesins are a type of virulence factor.

<span class="mw-page-title-main">Pertussis toxin</span> Group of toxins

Pertussis toxin (PT) is a protein-based AB5-type exotoxin produced by the bacterium Bordetella pertussis, which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection. Research suggests PT may have a therapeutic role in treating a number of common human ailments, including hypertension, viral infection, and autoimmunity.

<i>Bordetella pertussis</i> Species of bacterium causing pertussis or whooping cough

Bordetella pertussis is a Gram-negative, aerobic, pathogenic, encapsulated coccobacillus of the genus Bordetella, and the causative agent of pertussis or whooping cough. Like B. bronchiseptica, B. pertussis can express a flagellum-like structure, even if it has been historically categorized as a nonmotile bacteria. Its virulence factors include pertussis toxin, adenylate cyclase toxin, filamentous hæmagglutinin, pertactin, fimbria, and tracheal cytotoxin.

<i>Bordetella parapertussis</i> Species of bacterium

Bordetella parapertussis is a small Gram-negative bacterium of the genus Bordetella that is adapted to colonise the mammalian respiratory tract. Pertussis caused by B. parapertussis manifests with similar symptoms to B. pertussis-derived disease, but in general tends to be less severe. Immunity derived from B. pertussis does not protect against infection by B. parapertussis, however, because the O-antigen is found only on B. parapertussis. This antigen protects B. parapertussis against antibodies specific to B. pertussis, so the bacteria are free to colonize the host's lungs without being subject to attack by previous antibodies. These findings suggest B. parapertussis evolved in a host population that had already developed immunity to B. pertussis, where being able to evade B. pertussis immunity was an advantage.

The AB5 toxins are six-component protein complexes secreted by certain pathogenic bacteria known to cause human diseases such as cholera, dysentery, and hemolytic–uremic syndrome. One component is known as the A subunit, and the remaining five components are B subunits. All of these toxins share a similar structure and mechanism for entering targeted host cells. The B subunit is responsible for binding to receptors to open up a pathway for the A subunit to enter the cell. The A subunit is then able to use its catalytic machinery to take over the host cell's regular functions.

Porphyromonas gingivalis belongs to the phylum Bacteroidota and is a nonmotile, Gram-negative, rod-shaped, anaerobic, pathogenic bacterium. It forms black colonies on blood agar.

<span class="mw-page-title-main">NOD1</span> Protein receptor that recognizes bacterial molecules and stimulates an immune reaction

Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a protein receptor that in humans is encoded by the NOD1 gene. It recognizes bacterial molecules and stimulates an immune reaction.

<span class="mw-page-title-main">Peptidoglycan recognition protein 2</span> Protein-coding gene in the species Homo sapiens

Peptidoglycan recognition protein 2(PGLYRP2) is an enzyme, N-acetylmuramoyl-L-alanine amidase (NAMLAA), that hydrolyzes bacterial cell wall peptidoglycan and is encoded by the PGLYRP2 gene.

<span class="mw-page-title-main">Peptidoglycan recognition protein 1</span> Protein-coding gene in the species Homo sapiens

Peptidoglycan recognition protein 1, PGLYRP1, also known as TAG7, is an antibacterial and pro-inflammatory innate immunity protein that in humans is encoded by the PGLYRP1 gene.

<span class="mw-page-title-main">Clostridium difficile toxin A</span>

Clostridium difficile toxin A (TcdA) is a toxin generated by Clostridioides difficile, formerly known as Clostridium difficile. It is similar to Clostridium difficile Toxin B. The toxins are the main virulence factors produced by the gram positive, anaerobic, Clostridioides difficile bacteria. The toxins function by damaging the intestinal mucosa and cause the symptoms of C. difficile infection, including pseudomembranous colitis.

The RTX toxin superfamily is a group of cytolysins and cytotoxins produced by bacteria. There are over 1000 known members with a variety of functions. The RTX family is defined by two common features: characteristic repeats in the toxin protein sequences, and extracellular secretion by the type I secretion systems (T1SS). The name RTX refers to the glycine and aspartate-rich repeats located at the C-terminus of the toxin proteins, which facilitate export by a dedicated T1SS encoded within the rtx operon.

Adenylate cyclase toxin (CyaA) is released from bacterium Bordetella pertussis by the T1SS and released in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense.

<span class="mw-page-title-main">Peptidoglycan recognition protein</span>

Peptidoglycan recognition proteins (PGRPs) are a group of highly conserved pattern recognition receptors with at least one peptidoglycan recognition domain capable of recognizing the peptidoglycan component of the cell wall of bacteria. They are present in insects, mollusks, echinoderms and chordates. The mechanism of action of PGRPs varies between taxa. In insects, PGRPs kill bacteria indirectly by activating one of four unique effector pathways: prophenoloxidase cascade, Toll pathway, IMD pathway, and induction of phagocytosis. In mammals, PGRPs either kill bacteria directly by interacting with their cell wall or outer membrane, or hydrolyze peptidoglycan. They also modulate inflammation and microbiome and interact with host receptors.

<span class="mw-page-title-main">Imd pathway</span> Immune signaling pathway of insects

The Imd pathway is a broadly-conserved NF-κB immune signalling pathway of insects and some arthropods that regulates a potent antibacterial defence response. The pathway is named after the discovery of a mutation causing severe immune deficiency. The Imd pathway was first discovered in 1995 using Drosophila fruit flies by Bruno Lemaitre and colleagues, who also later discovered that the Drosophila Toll gene regulated defence against Gram-positive bacteria and fungi. Together the Toll and Imd pathways have formed a paradigm of insect immune signalling; as of September 2, 2019, these two landmark discovery papers have been cited collectively over 5000 times since publication on Google Scholar.

<span class="mw-page-title-main">Peptidoglycan recognition protein 3</span>

Peptidoglycan recognition protein 3 is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP3 gene.

<span class="mw-page-title-main">Peptidoglycan recognition protein 4</span>

Peptidoglycan recognition protein 4 is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP4 gene.

<span class="mw-page-title-main">Roman Dziarski</span> American scientist (born 1949)

Roman Dziarski is a Polish-born American immunologist and microbiologist. He is best known for his research on innate immunity and bacterial peptidoglycan, for discovering the family of human peptidoglycan recognition proteins, which comprises PGLYRP1, PGLYRP2, PGLYRP3, and PGLYRP4, and for defining the functions of these proteins.

References

  1. ↑ Cundell, DR; Kanthakumar, K; Taylor, GW; Goldman, WE; Flak, T; Cole, PJ; Wilson, R (1994). "Effect of tracheal cytotoxin from Bordetella pertussis on human neutrophil function in vitro". Infection and Immunity. 62 (2): 639–43. doi:10.1128/iai.62.2.639-643.1994. PMC   186151 . PMID   8300220.
  2. ↑ Koropatnick, TA; Engle, JT; Apicella, MA; Stabb, EV; Goldman, WE; McFall-Ngai, MJ (12 November 2004). "Microbial factor-mediated development in a host-bacterial mutualism". Science. 306 (5699): 1186–8. Bibcode:2004Sci...306.1186K. doi:10.1126/science.1102218. PMID   15539604. S2CID   41603462. Here, we report that Vibrio fischeri also releases TCT, which acts in synergy with lipopolysaccharide (LPS) to trigger tissue development in its mutualistic symbiosis with the squid Euprymna scolopes.
  3. ↑ Cloud, KA; Dillard, JP (June 2002). "A lytic transglycosylase of Neisseria gonorrhoeae is involved in peptidoglycan-derived cytotoxin production". Infection and Immunity. 70 (6): 2752–7. doi:10.1128/IAI.70.6.2752-2757.2002. PMC   127960 . PMID   12010959. A major peptidoglycan fragment released by gonococci is identical to the tracheal cytotoxin of Bordetella pertussis and has been shown to kill ciliated fallopian tube cells in organ culture.
  4. 1 2 3 Mattoo, S.; Cherry, J. D. (2005). "Molecular Pathogenesis, Epidemiology, and Clinical Manifestations of Respiratory Infections Due to Bordetella pertussis and Other Bordetella Subspecies". Clinical Microbiology Reviews. 18 (2): 326–82. doi:10.1128/CMR.18.2.326-382.2005. PMC   1082800 . PMID   15831828.
  5. 1 2 Parkhill, Julian; Sebaihia, Mohammed; Preston, Andrew; Murphy, Lee D; Thomson, Nicholas; Harris, David E; Holden, Matthew T G; Churcher, Carol M; et al. (2003). "Comparative analysis of the genome sequences of Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica". Nature Genetics. 35 (1): 32–40. doi: 10.1038/ng1227 . PMID   12910271.
  6. ↑ Goldman, W.E. and J.B. Baseman (March 1980). "Abstr. Ann. Meet. Am. Soc. Microbiol". Abstr. Ann. Meet. Am. Soc. Microbiol.[ page needed ]
  7. ↑ Goldman, William E.; Klapper, David G.; Baseman, Joel B. (1982-05-01). "Detection, isolation, and analysis of a released Bordetella pertussis product toxic to cultured tracheal cells". Infection and Immunity. 36 (2): 782–94. doi:10.1128/iai.36.2.782-794.1982. PMC   351298 . PMID   6177637.
  8. ↑ Cookson, BT; Tyler, AN; Goldman, WE (1989). "Primary structure of the peptidoglycan-derived tracheal cytotoxin of Bordetella pertussis". Biochemistry. 28 (4): 1744–9. doi:10.1021/bi00430a048. PMID   2541765.
  9. ↑ Wilson, R; Read, R; Thomas, M; Rutman, A; Harrison, K; Lund, V; Cookson, B; Goldman, W; et al. (1991-01-01). "Effects of Bordetella pertussis infection on human respiratory epithelium in vivo and in vitro". Infection and Immunity. 59 (1): 337–45. doi:10.1128/iai.59.1.337-345.1991. PMC   257746 . PMID   1987048.
  10. ↑ Luker, K. E.; Collier, J. L.; Kolodziej, E. W.; Marshall, G. R.; Goldman, W. E. (1993). "Bordetella pertussis Tracheal Cytotoxin and Other Muramyl Peptides: Distinct Structure-Activity Relationships for Respiratory Epithelial Cytopathology". Proceedings of the National Academy of Sciences. 90 (6): 2365–2369. Bibcode:1993PNAS...90.2365L. doi: 10.1073/pnas.90.6.2365 . PMC   46087 . PMID   8460147.
  11. ↑ Jacobs, C; Joris, B; Jamin, M; Klarsov, K; Van Beeumen, J; Mengin-Lecreulx, D; Van Heijenoort, J; Park, JT; et al. (1995). "AmpD, essential for both beta-lactamase regulation and cell wall recycling, is a novel cytosolic N-acetylmuramyl-L-alanine amidase". Molecular Microbiology. 15 (3): 553–9. doi:10.1111/j.1365-2958.1995.tb02268.x. PMID   7783625. S2CID   40169153.
  12. ↑ Wilson, R; Read, R; Thomas, M; Rutman, A; Harrison, K; Lund, V; Cookson, B; Goldman, W; et al. (1991). "Effects of Bordetella pertussis infection on human respiratory epithelium in vivo and in vitro". Infection and Immunity. 59 (1): 337–45. doi:10.1128/iai.59.1.337-345.1991. PMC   257746 . PMID   1987048.
  13. ↑ Swaminathan, C. P.; Brown, P. H.; Roychowdhury, A.; Wang, Q.; Guan, R.; Silverman, N.; Goldman, W. E.; Boons, G.-J.; Mariuzza, R. A. (2006). "Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs)". Proceedings of the National Academy of Sciences. 103 (3): 684–9. Bibcode:2006PNAS..103..684S. doi: 10.1073/pnas.0507656103 . PMC   1334652 . PMID   16407132.
  14. ↑ Melvin, Jeffrey A.; Scheller, Erich V.; Miller, Jeff F.; Cotter, Peggy A. (2014-04-01). "Bordetella pertussis pathogenesis: current and future challenges". Nature Reviews Microbiology. 12 (4): 274–288. doi:10.1038/nrmicro3235. ISSN   1740-1526. PMC   4205565 . PMID   24608338.
  15. ↑ Coote, JG (2001). Environmental sensing mechanisms in Bordetella. Advances in Microbial Physiology. Vol. 44. pp. 141–81. doi:10.1016/S0065-2911(01)44013-6. ISBN   9780120277445. PMID   11407112.
  16. ↑ Swaminathan, C. P.; Brown, PH; Roychowdhury, A; Wang, Q; Guan, R; Silverman, N; Goldman, WE; Boons, GJ; Mariuzza, RA (2006). "Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs)". Proceedings of the National Academy of Sciences. 103 (3): 684–9. Bibcode:2006PNAS..103..684S. doi: 10.1073/pnas.0507656103 . PMC   1334652 . PMID   16407132.
  17. ↑ Humann, Jessica; Lenz, Laurel L. (2009). "Bacterial Peptidoglycan-Degrading Enzymes and Their Impact on Host Muropeptide Detection". Journal of Innate Immunity. 1 (2): 88–97. doi:10.1159/000181181. PMC   2659621 . PMID   19319201.
  18. ↑ Magalhaes, Joao Gamelas; Philpott, Dana J; Nahori, Marie-Anne; Jéhanno, Muguette; Fritz, Joerg; Bourhis, Lionel Le; Viala, Jérôme; Hugot, Jean-Pierre; et al. (2005). "Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin". EMBO Reports. 6 (12): 1201–7. doi:10.1038/sj.embor.7400552. PMC   1369207 . PMID   16211083.
  19. ↑ Skerry, C; Goldman, WE; Carbonetti, NH (February 2019). "Peptidoglycan Recognition Protein 4 Suppresses Early Inflammatory Responses to Bordetella pertussis and Contributes to Sphingosine-1-Phosphate Receptor Agonist-Mediated Disease Attenuation". Infection and Immunity. 87 (2). doi:10.1128/IAI.00601-18. PMC   6346131 . PMID   30510103.
  20. ↑ Chang, CI; Chelliah, Y; Borek, D; Mengin-Lecreulx, D; Deisenhofer, J (24 March 2006). "Structure of tracheal cytotoxin in complex with a heterodimeric pattern-recognition receptor". Science. 311 (5768): 1761–4. Bibcode:2006Sci...311.1761C. doi:10.1126/science.1123056. PMID   16556841. S2CID   25416989.
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