Tetanus toxin

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Tetanus toxin
PDB 1a8d EBI.jpg
Tetanus Toxin Heavy Chain C Fragment ( PDB: 1a8d ​)
Identifiers
Organism Clostridium tetani E88
SymboltetX
Entrez 24255210
RefSeq (Prot) WP_011100836.1
UniProt P04958
Other data
Chromosome Genomic: 0.07 - 0.07 Mb
Search for
Structures Swiss-model
Domains InterPro
Tentoxilysin
Identifiers
EC no. 3.4.24.68
CAS no. 107231-12-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Search
PMC articles
PubMed articles
NCBI proteins
Structure of tetanospasmin Diagram of structure of tetanospasmin.png
Structure of tetanospasmin
Mechanism of action of tetanospasmin Mechanism of action of tetanospasmin.gif
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.

Contents

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

Distribution

Tetanus toxin spreads through tissue spaces into the lymphatic and 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 protein has a molecular weight of 150  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 polysialogangliosides, similarly to the C. botulinum neurotoxin. It also binds to another poorly characterized 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. [14] [15] Once the toxin has been translocated into the cytosol, chemical reduction of the disulfide bond to separate thiols occurs, mainly by the enzyme NADPH-thioredoxin reductase-thioredoxin. The light chain is then free to cleave the Gln76-Phe77 bond of synaptobrevin. [16] Cleavage of synaptobrevin affects the stability of the SNARE core by restricting it from entering the low-energy conformation, which is the target for NSF binding. [17] Synaptobrevin is an integral V-SNARE necessary for vesicle fusion to membranes. The final target of TeNT is the cleavage of synaptobrevin and, even in low doses, has the effect of interfering with exocytosis of neurotransmitters from inhibitory interneurons. The blockage of the neurotransmitters γ-aminobutyric acid (GABA) and glycine is the direct cause of the physiological effects that TeNT induces. GABA inhibits motor neurons, so by blocking GABA, tetanus toxin causes violent spastic paralysis. [18] The action of the A-chain also stops the affected neurons from releasing excitatory transmitters, [19] by degrading the protein synaptobrevin 2. [20] The combined consequence is dangerous overactivity in the muscles from the smallest sensory stimuli, as the damping of 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 neurotransmitters, including glycine and gamma-aminobutyric acid. These inhibitory neurotransmitters inhibit the alpha motor neurons. With diminished inhibition, the resting firing rate of the alpha motor neuron increases, producing rigidity, unopposed muscle contraction and spasm. Characteristic features are risus sardonicus (a rigid smile), trismus (commonly known as "lock-jaw"), and opisthotonus (rigid, arched back). Seizures may occur, and the autonomic nervous system may also be affected. Tetanospasmin appears to prevent the release of neurotransmitters by selectively cleaving a component of synaptic vesicles called synaptobrevin II. [21] Loss of inhibition also affects preganglionic sympathetic neurons in the lateral 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 toxoid derived from the toxin, as in the tetanus vaccine and some combination vaccines (such as 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.

Related Research Articles

<span class="mw-page-title-main">Chemical synapse</span> Biological junctions through which neurons signals can be sent

Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

<span class="mw-page-title-main">Botulinum toxin</span> Neurotoxic protein produced by Clostridium botulinum

Botulinum toxin, or botulinum neurotoxin, is a highly potent neurotoxic protein produced by the bacterium Clostridium botulinum and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction, thus causing flaccid paralysis. The toxin causes the disease botulism. The toxin is also used commercially for medical and cosmetic purposes. Botulinum toxin is an acetylcholine release inhibitor and a neuromuscular blocking agent.

<span class="mw-page-title-main">Tetanus</span> Bacterial infection characterized by muscle spasms

Tetanus, also known as lockjaw, is a bacterial infection caused by Clostridium tetani and characterized by muscle spasms. In the most common type, the spasms begin in the jaw, and then progress to the rest of the body. Each spasm usually lasts for a few minutes. Spasms occur frequently for three to four weeks. Some spasms may be severe enough to fracture bones. Other symptoms of tetanus may include fever, sweating, headache, trouble swallowing, high blood pressure, and a fast heart rate. Onset of symptoms is typically 3 to 21 days following infection. Recovery may take months; about 10% of cases prove to be fatal.

<span class="mw-page-title-main">Neurotoxin</span> Toxin harmful to nervous tissue

Neurotoxins are toxins that are destructive to nerve tissue. Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. Common examples of neurotoxins include lead, ethanol, glutamate, nitric oxide, botulinum toxin, tetanus toxin, and tetrodotoxin. Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.

<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.

<span class="mw-page-title-main">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

<span class="mw-page-title-main">Synaptic vesicle</span> Neurotransmitters that are released at the synapse

In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell. The area in the axon that holds groups of vesicles is an axon terminal or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz. In the visual cortex of the human brain, synaptic vesicles have an average diameter of 39.5 nanometers (nm) with a standard deviation of 5.1 nm.

<span class="mw-page-title-main">End-plate potential</span> Voltages associated with muscle fibre

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

<span class="mw-page-title-main">SNARE protein</span> Protein family

SNARE proteins – "SNAPREceptors" – are a large protein family consisting of at least 24 members in yeasts, more than 60 members in mammalian cells, and some numbers in plants. The primary role of SNARE proteins is to mediate the fusion of vesicles with the target membrane; this notably mediates exocytosis, but can also mediate the fusion of vesicles with membrane-bound compartments. The best studied SNAREs are those that mediate the release of synaptic vesicles containing neurotransmitters in neurons. These neuronal SNAREs are the targets of the neurotoxins responsible for botulism and tetanus produced by certain bacteria.

<span class="mw-page-title-main">Synaptobrevin</span>

Synaptobrevins are small integral membrane proteins of secretory vesicles with molecular weight of 18 kilodalton (kDa) that are part of the vesicle-associated membrane protein (VAMP) family.

<span class="mw-page-title-main">Neurotransmission</span> Impulse transmission between neurons

Neurotransmission is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron, and bind to and react with the receptors on the dendrites of another neuron a short distance away. A similar process occurs in retrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly at GABAergic and glutamatergic synapses.

Tetanolysin is a toxin produced by Clostridium tetani bacteria. Its function is unknown, but it is believed to contribute to the pathogenesis of tetanus. The other C. tetani toxin, tetanospasmin, is more definitively linked to tetanus. It is sensitive to oxygen.

Taipoxin is a potent myo- and neurotoxin that was isolated from the venom of the coastal taipan Oxyuranus scutellatus or also known as the common taipan. Taipoxin like many other pre-synaptic neurotoxins are phospholipase A2 (PLA2) toxins, which inhibit/complete block the release of the motor transmitter acetylcholine and lead to death by paralysis of the respiratory muscles (asphyxia). It is the most lethal neurotoxin isolated from any snake venom to date.

<i>Clostridium tetani</i> Common soil bacterium and the causative agent of tetanus

Clostridium tetani is a common soil bacterium and the causative agent of tetanus. Vegetative cells of Clostridium tetani are usually rod-shaped and up to 2.5 μm long, but they become enlarged and tennis racket- or drumstick-shaped when forming spores. C. tetani spores are extremely hardy and can be found globally in soil or in the gastrointestinal tract of animals. If inoculated into a wound, C. tetani can grow and produce a potent toxin, tetanospasmin, which interferes with motor neurons, causing tetanus. The toxin's action can be prevented with tetanus toxoid vaccines, which are often administered to children worldwide.

<span class="mw-page-title-main">Clostridium enterotoxin</span>

Clostridium enterotoxins are toxins produced by Clostridium species. Clostridial species are one of the major causes of food poisoning/gastrointestinal illnesses. They are anaerobic, gram-positive, spore-forming rods that occur naturally in the soil. Among the family are: Clostridium botulinum, which produces one of the most potent toxins in existence; Clostridium tetani, causative agent of tetanus; and Clostridium perfringens, commonly found in wound infections and diarrhea cases.

Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. Endotoxins most commonly refer to the lipopolysaccharide (LPS) or lipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. The botulinum toxin, which is primarily produced by Clostridium botulinum and less frequently by other Clostridium species, is the most toxic substance known in the world. However, microbial toxins also have important uses in medical science and research. Currently, new methods of detecting bacterial toxins are being developed to better isolate and understand these toxins. Potential applications of toxin research include combating microbial virulence, the development of novel anticancer drugs and other medicines, and the use of toxins as tools in neurobiology and cellular biology.

Munc-18 proteins are the mammalian homologue of UNC-18 and are a member of the Sec1/Munc18-like (SM) protein family. Munc-18 proteins have been identified as essential components of the synaptic vesicle fusion protein complex and are crucial for the regulated exocytosis of neurons and neuroendocrine cells.

<span class="mw-page-title-main">Thomas C. Südhof</span> German-American biochemist

Thomas Christian Südhof, ForMemRS, is a German-American biochemist known for his study of synaptic transmission. Currently, he is a professor in the school of medicine in the department of molecular and cellular physiology, and by courtesy in neurology, and in psychiatry and behavioral sciences at Stanford University.

<span class="mw-page-title-main">Soluble NSF attachment protein</span> Protein family

Soluble N-ethylmaleimide-Sensitive Factor Attachment Proteins are a family of cytosolic adaptor proteins involved in vesicular fusion at membranes during intracellular transport and exocytosis. SNAPs interact with proteins of the SNARE complex and NSF to play a key role in recycling the components of the fusion complex. SNAPs are involved in the priming of the vesicle fusion complex during assembly, as well as in the disassembly following a vesicle fusion event. Following membrane fusion, the tethering SNARE proteins complex disassembles in response to steric changes originating from the ATPase NSF. The energy provided by NSF is transferred throughout the SNARE complex and SNAP, allowing the proteins to untangle, and recycled for future fusion events. Mammals have three SNAP genes: α-SNAP, β-SNAP, and γ-SNAP. α- and γ-SNAP are expressed throughout the body, while β-SNAP is specific to the brain. The yeast homolog of the human SNAP is Sec17, the structural diagram of which is included on this page.

Edwin R. Chapman is an American biochemist known for his work on Ca2+-triggered exocytosis. He currently serves as the Ricardo Miledi Professor of Neuroscience at the University of Wisconsin–Madison, where he is also an investigator of the Howard Hughes Medical Institute (HHMI).

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. ↑ Willey J (2009). Prescott's Principles of Microbiology . New York City, NY: McGraw-Hill. pp.  481. ISBN   978-0-07-337523-6.
  6. ↑ Farrar JJ, Yen LM, Cook T, Fairweather N, Binh N, Parry J, et al. (September 2000). "Tetanus". Journal of Neurology, Neurosurgery, and Psychiatry. 69 (3): 292–301. doi:10.1136/jnnp.69.3.292. PMC   1737078 . PMID   10945801.
  7. ↑ Lalli G, Gschmeissner S, Schiavo G (November 2003). "Myosin Va and microtubule-based motors are required for fast axonal retrograde transport of tetanus toxin in motor neurons". Journal of Cell Science. 116 (Pt 22): 4639–4650. doi: 10.1242/jcs.00727 . PMID   14576357.
  8. ↑ Eisel U, Jarausch W, Goretzki K, Henschen A, Engels J, Weller U, et al. (October 1986). "Tetanus toxin: primary structure, expression in E. coli, and homology with botulinum toxins". The EMBO Journal. 5 (10): 2495–2502. doi:10.1002/j.1460-2075.1986.tb04527.x. PMC   1167145 . PMID   3536478.
  9. ↑ Popp D, Narita A, Lee LJ, Ghoshdastider U, Xue B, Srinivasan R, et al. (June 2012). "Novel actin-like filament structure from Clostridium tetani". The Journal of Biological Chemistry. 287 (25): 21121–21129. doi: 10.1074/jbc.M112.341016 . PMC   3375535 . PMID   22514279.
  10. ↑ "Advanced Search for UniProt ID P04958". Protein Databank in Europe (PDBe).
  11. ↑ Munro P, Kojima H, Dupont JL, Bossu JL, Poulain B, Boquet P (November 2001). "High sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein". Biochemical and Biophysical Research Communications. 289 (2): 623–629. doi:10.1006/bbrc.2001.6031. PMID   11716521.
  12. 1 2 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. doi:10.1016/0009-3084(96)02529-7. PMID   9450318.
  13. ↑ Yeh FL, Dong M, Yao J, Tepp WH, Lin G, Johnson EA, et al. (November 2010). "SV2 mediates entry of tetanus neurotoxin into central neurons". PLOS Pathogens. 6 (11): e1001207. doi: 10.1371/journal.ppat.1001207 . PMC   2991259 . PMID   21124874.
  14. ↑ Pirazzini M, Rossetto O, Bertasio C, Bordin F, Shone CC, Binz T, et al. (January 2013). "Time course and temperature dependence of the membrane translocation of tetanus and botulinum neurotoxins C and D in neurons". Biochemical and Biophysical Research Communications. 430 (1): 38–42. doi:10.1016/j.bbrc.2012.11.048. PMID   23200837.
  15. ↑ Burns JR, Baldwin MR (August 2014). "Tetanus neurotoxin utilizes two sequential membrane interactions for channel formation". The Journal of Biological Chemistry. 289 (32): 22450–22458. doi: 10.1074/jbc.m114.559302 . PMC   4139251 . PMID   24973217.
  16. ↑ Pirazzini M, Bordin F, Rossetto O, Shone CC, Binz T, Montecucco C (January 2013). "The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals". FEBS Letters. 587 (2): 150–155. doi: 10.1016/j.febslet.2012.11.007 . PMID   23178719.[ permanent dead link ]
  17. ↑ Pellegrini LL, O'Connor V, Lottspeich F, Betz H (October 1995). "Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion". The EMBO Journal. 14 (19): 4705–4713. doi:10.1002/j.1460-2075.1995.tb00152.x. PMC   394567 . PMID   7588600.
  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. ↑ Kanda K, Takano K (February 1983). "Effect of tetanus toxin on the excitatory and the inhibitory post-synaptic potentials in the cat motoneurone". The Journal of Physiology. 335: 319–333. doi:10.1113/jphysiol.1983.sp014536. PMC   1197355 . PMID   6308220.
  20. ↑ Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, et al. (October 1992). "Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin". Nature. 359 (6398): 832–835. Bibcode:1992Natur.359..832S. doi:10.1038/359832a0. PMID   1331807. S2CID   4241066.
  21. ↑ Todar K (2005). "Pathogenic Clostridia, including Botulism and Tetanus". Todar's Online Textbook of Bacteriology. Retrieved 24 June 2018.
  22. ↑ Loscalzo J, Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL (2008). Harrison's principles of internal medicine. McGraw-Hill Medical. 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. ↑ Whikehart DR (2003). Biochemistry of the Eye (2nd ed.). Boston: Butterworth-Heinemann. pp. 107–108. ISBN   0-7506-7152-1.
  25. ↑ Popoff MR (March 2020). "Tetanus in animals". Journal of Veterinary Diagnostic Investigation. 32 (2). SAGE Publications: 184–191. doi:10.1177/1040638720906814. PMC   7081504 . PMID   32070229.
  26. ↑ Hao NV, Huyen NN, Ny NT, Trang VT, Hoang NV, Thuy DB, et al. (June 2021). "The Role of the Gastrointestinal Tract in Toxigenic Clostridium tetani Infection: A Case-Control Study". The American Journal of Tropical Medicine and Hygiene. 105 (2). American Society of Tropical Medicine and Hygiene: 494–497. doi:10.4269/ajtmh.21-0146. PMC   8437200 . PMID   34181568.

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