Tetanus toxin

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Tetanospasmin
)
Tetanus toxin
UniProt
P04958
Other data
ChromosomeGenomic: 0.07 - 0.07 Mb
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StructuresSwiss-model
DomainsInterPro
Tentoxilysin
Identifiers
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
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NCBIproteins
Structure of tetanospasmin
Mechanism of action of tetanospasmin

Tetanus toxin (TeNT) is an extremely potent neurotoxin produced by the vegetative cell of Clostridium tetani[1] in anaerobic conditions, causing tetanus. It has no known function for clostridia in the soil environment where they are normally encountered. It is also called spasmogenic toxin, tentoxilysin, tetanospasmin or, tetanus neurotoxin. The LD50 of this toxin has been measured to be approximately 2.5–3 ng/kg,[2][3] making it second only to the related botulinum toxin (LD50 2 ng/kg)[4] as the deadliest toxin in the world. However, these tests are conducted solely on mice, which may react to the toxin differently from humans and other animals.

C. tetani also produces the exotoxin tetanolysin, a hemolysin, that causes destruction of tissues.[5]

Distribution

Tetanus toxin spreads through tissue spaces into the

vascular systems. It enters the nervous system at the neuromuscular junctions and migrates through nerve trunks and into the central nervous system (CNS) by retrograde axonal transport by using dyneins.[6][7]

Structure

The tetanus toxin

kDa. It is translated from the tetX gene as one protein which is subsequently cleaved into two parts: a 100 kDa heavy or B-chain and a 50 kDa light or A-chain. The chains are connected by a disulfide bond
.

The TetX gene encoding this protein is located on the PE88 plasmid.[8][9]

Several structures of the binding domain and the peptidase domain have been solved by X-ray crystallography and deposited in the PDB.[10]

Mechanism of action

The mechanism of TeNT action can be broken down and discussed in these different steps:

Transport
  1. Specific binding in the periphery neurons
  2. Retrograde axonal transport to the CNS inhibitory interneurons
  3. Transcytosis from the axon into the inhibitory interneurons
Action
  1. Temperature- and pH-mediated translocation of the light chain into the cytosol
  2. Reduction of the disulfide bridge to thiols, severing the link between the light and heavy chain
  3. Cleavage of synaptobrevin at -Gln76-Phe- bond

The first three steps outline the travel of tetanus toxin from the peripheral nervous system to where it is taken up to the CNS and has its final effect. The last three steps document the changes necessary for the final mechanism of the neurotoxin.

Transport to the CNS inhibitory interneurons begins with the B-chain mediating the neurospecific binding of TeNT to the nerve terminal membrane. It binds to GT1b polysialo

GPI-anchored protein receptor more specific to TeNT.[11][12] Both the ganglioside and the GPI-anchored protein are located in lipid microdomains and both are requisite for specific TeNT binding.[12] Once it is bound, the neurotoxin is then endocytosed into the nerve and begins to travel through the axon to the spinal neurons. The next step, transcytosis from the axon into the CNS inhibitory interneuron, is one of the least understood parts of TeNT action. At least two pathways are involved, one that relies on the recycling of synaptic vesicle 2 (SV2) system and one that does not.[13]

Once the vesicle is in the inhibitory interneuron, its translocation is mediated by pH and temperature, specifically a low or acidic pH in the vesicle and standard physiological temperatures.

motor reflexes
is inhibited, leading to generalized contractions of the agonist and antagonist musculature, termed a "tetanic spasm".

Clinical significance

The clinical manifestations of tetanus are caused when tetanus toxin blocks inhibitory impulses, by interfering with the release of

gray matter of the spinal cord and produces sympathetic hyperactivity and high circulating catecholamine levels. Hypertension and tachycardia alternating with hypotension and bradycardia may develop.[22][23]

Tetanic spasms can occur in a distinctive form called

opisthotonos and be sufficiently severe to fracture long bones. The shorter nerves are the first to be inhibited, which leads to the characteristic early symptoms in the face and jaw, risus sardonicus and lockjaw
.

Immunity and vaccination

Due to its extreme potency, even a lethal dose of tetanospasmin may be insufficient to provoke an immune response. Naturally acquired tetanus infections thus do not usually provide immunity to subsequent infections. Immunization (which is impermanent and must be repeated periodically) instead uses the less deadly

DTP
).

Evolution

Very little has been written or researched on how and why tetanospasmin evolved in animals. The toxin is highly specific to muscular neurons in higher animals and is carried by a plasmid which implies that the host bacterium acquired the plasmid through horizontal gene transfer from another source organism as is the case of most plasmid based toxins such as shigatoxin. Although tetanospasmin is now classified as an extremely potent neurotoxin, its evolutionary origins may indicate it may have served an entirely different function in early animal life. It is routinely carried by anaerobic organisms and early life on earth was typically capable of both aerobic and anaerobic respiration. Human DNA still contains all the genes necessary for anaerobic respiration and one example is the lens cells of the human eye, which still operate in anaerobic mode.[24]

Most lower animals, and even some mammals are capable of anaerobic respiration during their hibernation phases. The spasms typically caused by this toxin mimic cardiac rhythms in skeletal muscles in most reptiles exposed to the toxin and would provide an evolutionary advantage to a hibernating reptile by keeping blood moving slowly around the organism while in hibernation mode if the organism switched to anaerobic respiration. This theory is supported by the fact that tetanus bacteria use a "pump and dump" strategy by secreting the toxin inside a plasmid membrane then exocysing the plasmid vacuole into target tissue. The toxin is not immediately released typically. [25] Higher mammals host this bacteria as a common component of intestinal gut flora and mouth bacteria without any ill effects and it only becomes a problem in anaerobic conditions.[26]

It has no currently known function in the bacterium's host environment which is soil and manure and is harmless to any competing organisms. It only affects higher animals which have neuro muscular junctions which makes its very existence a mystery to modern science.

References

  1. ^ "Tetanospasmin" at Dorland's Medical Dictionary
  2. ^ "Pinkbook | Tetanus | Epidemiology of Vaccine Preventable Diseases". CDC. Retrieved 2017-01-18.
  3. ^ "Toxin Table". Environmental Health & Safety » University of Florida. Archived from the original on 2017-01-18. Retrieved 2017-01-18.
  4. ^ "Botulism". World Health Organization. Retrieved 2017-01-18.
  5. ISBN 978-0-07-337523-6
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  6. PMID 10945801
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  7. PMID 14576357
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  8. PMID 3536478
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  9. PMID 22514279
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  10. ^ "Advanced Search for UniProt ID P04958". Protein Databank in Europe (PDBe).
  11. PMID 11716521
    .
  12. ^ a b Winter A, Ulrich WP, Wetterich F, Weller U, Galla HJ (June 1996). "Gangliosides in phospholipid bilayer membranes: interaction with tetanus toxin". Chemistry and Physics of Lipids. 81 (1): 21–34.
    PMID 9450318
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  13. PMID 21124874
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  14. PMID 23200837
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  15. PMID 24973217
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  16. PMID 23178719.[permanent dead link
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  17. PMID 7588600
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  18. ^ Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease (Professional: Expert Consult - Online Kindle ed.). Elsevier Health.
  19. PMID 6308220
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  20. S2CID 4241066
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  21. ^ Todar K (2005). "Pathogenic Clostridia, including Botulism and Tetanus". Todar's Online Textbook of Bacteriology. Retrieved 24 June 2018.
  22. ISBN 978-0-07-146633-2
    .
  23. ^ Yabes Jr JM, McLaughlin R. Brusch JL (ed.). "Tetanus in Emergency Medicine". Emedicine. Retrieved 2011-09-01.
  24. ISBN 0-7506-7152-1
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  25. PMID 32070229
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  26. PMID 34181568
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Further reading

External links
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