Tetanus toxin (TeNT) is an extremely potent
neurotoxin
Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature ner ...
produced by the vegetative cell of ''
Clostridium tetani
''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 ...
'' in
anaerobic
Anaerobic means "living, active, occurring, or existing in the absence of free oxygen", as opposed to aerobic which means "living, active, or occurring only in the presence of oxygen." Anaerobic may also refer to:
* Anaerobic adhesive, a bonding a ...
conditions, causing
tetanus
Tetanus, also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'', and is 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 ...
. 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 LD
50 of this toxin has been measured to be approximately 2.5–3 ng/kg, making it second only to the related
botulinum toxin
Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromusc ...
(LD
50 2 ng/kg) 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
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, simi ...
tetanolysin, a hemolysin, that causes destruction of tissues.
Distribution
Tetanus toxin spreads through tissue spaces into the
lymphatic
Lymph (from Latin, , meaning "water") is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues to ...
and
vascular system
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
s. It enters the nervous system at the
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
s and migrates through nerve trunks and into the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS) by retrograde axonal transport by using
dynein
Dyneins are a family of cytoskeletal motor proteins that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargos, provides forces and displacements importa ...
s.
Structure
The tetanus toxin
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
has a molecular weight of 150
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
. 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
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
.
* The B-chain binds to disialo
ganglioside
A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. ''N''-acetylneuraminic acid, NANA) linked on the sugar chain. NeuNAc, an acetylated derivative of the carbohydrate si ...
s (GD2 and GD1b) on the neuronal membrane and contains a translocation domain which aids the movement of the protein across that membrane and into the neuron.
* The A-chain, an M27-family zinc
endopeptidase
Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids. For this re ...
, attacks the
vesicle-associated membrane protein
Vesicle associated membrane proteins (VAMP) are a family of SNARE proteins with similar structure, and are mostly involved in vesicle fusion.
* VAMP1 and VAMP2 proteins known as synaptobrevins are expressed in brain and are constituents of t ...
(VAMP).
The TetX gene encoding this protein is located on the PE88 plasmid.
Several structures of the binding domain and the peptidase domain have been solved by
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
and deposited in the
PDB. A summary of these structures is available using th
UniPDBapplication a
PDBe for example or .
Mechanism of action
The mechanism of TeNT action can be broken down and discussed in these different steps:
;Transport
:# Specific binding in the
periphery neurons
:#
Retrograde axonal transport to the CNS
inhibitory interneurons
:#
Transcytosis Transcytosis (also known as cytopempsis) is a type of transcellular transport in which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ...
from the axon into the inhibitory interneurons
;Action
:# Temperature- and pH-mediated translocation of the light chain into the cytosol
:#
Reduction of the disulfide bridge to
thiol
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
s, severing the link between the light and heavy chain
:# Cleavage of synaptobrevin at -Gln
76-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
gangliosides
A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. ''N''-acetylneuraminic acid, NANA) linked on the sugar chain. NeuNAc, an acetylated derivative of the carbohydrate sial ...
, similarly to the ''C. botulinum'' neurotoxin. It also binds to another poorly characterized
GPI-anchored protein
Lipid-anchored proteins (also known as lipid-linked proteins) are proteins located on the surface of the cell membrane that are covalently attached to lipids embedded within the cell membrane. These proteins insert and assume a place in the bilay ...
receptor more specific to TeNT.
[
] Both the ganglioside and the GPI-anchored protein are located in
lipid microdomains and both are requisite for specific TeNT binding.
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.
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.
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.
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.
Synaptobrevin is an integral
V-SNARE necessary for vesicle fusion to membranes. The final target of TeNT is the cleavage of
synaptobrevin
Synaptobrevins (''synaptobrevin isotypes 1-2'') 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.
Synaptobrevi ...
and, even in low doses, has the effect of interfering with
exocytosis
Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...
of
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s from inhibitory
interneuron
Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. I ...
s. The blockage of the neurotransmitters
γ-aminobutyric acid (GABA) and
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
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. The action of the A-chain also stops the affected neurons from releasing excitatory transmitters, by degrading the protein
synaptobrevin 2.
The combined consequence is dangerous overactivity in the
muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
s from the smallest sensory stimuli, as the damping of
motor reflex
Tendon reflex (or T-reflex) may refer to:
*The stretch reflex or muscle stretch reflex (MSR), when the stretch is created by a blow upon a muscle tendon. This is the commonly used definition of the term. Albeit a misnomer, in this sense a common ...
es 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
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s, including
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
and
gamma-aminobutyric acid. These inhibitory neurotransmitters inhibit the
alpha motor neuron
Alpha (α) motor neurons (also called alpha motoneurons), are large, multipolar lower motor neurons of the brainstem and spinal cord. They innervate extrafusal muscle fibers of skeletal muscle and are directly responsible for initiating their con ...
s. 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
''Risus sardonicus'' or rictus grin is a highly characteristic, abnormal, sustained spasm of the facial muscles that appears to produce grinning. It may be caused by tetanus, strychnine poisoning, or Wilson's disease, and has been reported after j ...
(a rigid smile),
trismus
Trismus, commonly called ''lockjaw'' as associated with tetanus, is a condition of limited jaw mobility. It may be caused by spasm of the muscles of mastication or a variety of other causes. Temporary trismus occurs much more frequently than perma ...
(commonly known as "lock-jaw"), and
opisthotonus
Opisthotonus or opisthotonos (from grc, ὄπισθεν, translit=opisthen, lit=behind and grc, τόνος, translit=tonos, lit=tension, label=none) is a state of severe hyperextension and spasticity in which an individual's head, neck and spinal ...
(rigid, arched back).
Seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...
may occur, and the
autonomic nervous system
The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...
may also be affected. Tetanospasmin appears to prevent the release of neurotransmitters by selectively cleaving a component of synaptic vesicles called
synaptobrevin
Synaptobrevins (''synaptobrevin isotypes 1-2'') 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.
Synaptobrevi ...
II.
Loss of inhibition also affects preganglionic sympathetic neurons in the lateral
gray matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is distinguis ...
of the spinal cord and produces sympathetic hyperactivity and high circulating
catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a subst ...
levels.
Hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
and
tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...
alternating with
hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
and
bradycardia
Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...
may develop.
Tetanic spasms can occur in a distinctive form called ''
opisthotonos
Opisthotonus or opisthotonos (from grc, ὄπισθεν, translit=opisthen, lit=behind and grc, τόνος, translit=tonos, lit=tension, label=none) is a state of severe hyperextension and spasticity in which an individual's head, neck and spinal ...
'' 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
''Risus sardonicus'' or rictus grin is a highly characteristic, abnormal, sustained spasm of the facial muscles that appears to produce grinning. It may be caused by tetanus, strychnine poisoning, or Wilson's disease, and has been reported after j ...
'' and
lockjaw.
The toxin bind to the neurons is irreversible
and nerve function can only be returned by the growth of new terminals and synapses.
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
A toxoid is an inactivated toxin (usually an exotoxin) whose toxicity has been suppressed either by chemical (formalin) or heat treatment, while other properties, typically immunogenicity, are maintained. Toxins are secreted by bacteria, wherea ...
derived from the toxin, as in the
tetanus vaccine
Tetanus vaccine, also known as tetanus toxoid (TT), is a toxoid vaccine used to prevent tetanus. During childhood, five doses are recommended, with a sixth given during adolescence.
After three doses, almost everyone is initially immune, but a ...
and some
combination vaccines (such as
DTP).
References
External links
*
*
*
*
Neurotoxin in Toxicon The journey of tetanus and botulinum neurotoxins in neurons How do tetanus and botulinum toxins bind to neuronal membranes?
{{Enzymes
EC 3.4.24
Neurotoxins
Bacterial toxins
Tetanus
Proteins