Clostridium tetani
Encyclopedia
Clostridium tetani is a rod-shaped, anaerobic
Anaerobic organism
An anaerobic organism or anaerobe is any organism that does not require oxygen for growth. It could possibly react negatively and may even die if oxygen is present...

 bacterium of the genus Clostridium
Clostridium
Clostridium is a genus of Gram-positive bacteria, belonging to the Firmicutes. They are obligate anaerobes capable of producing endospores. Individual cells are rod-shaped, which gives them their name, from the Greek kloster or spindle...

. Like other Clostridium species, it is Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

, and its appearance on a gram stain resembles tennis rackets or drumsticks. C. tetani is found as spores
Endospore
An endospore is a dormant, tough, and temporarily non-reproductive structure produced by certain bacteria from the Firmicute phylum. The name "endospore" is suggestive of a spore or seed-like form , but it is not a true spore . It is a stripped-down, dormant form to which the bacterium can reduce...

 in soil or in the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

 of animals. C. tetani produces a potent biological toxin, tetanospasmin
Tetanospasmin
Tetanus toxin is an extremely potent neurotoxin produced by the vegetative cell of Clostridium tetani 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, tetanospasmin or...

, and is the causative agent of tetanus
Tetanus
Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...

, a disease characterized by painful muscular spasms that can lead to respiratory failure and, in up to 40% of cases, death.

History

Tetanus
Tetanus
Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...

 was known to ancient people, who recognized the relationship between wounds and fatal muscle spasms. In 1884, Arthur Nicolaier isolated the strychnine
Strychnine
Strychnine is a highly toxic , colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion...

-like toxin of tetanus from free-living, anaerobic soil bacteria. The etiology of the disease was further elucidated in 1890 by Antonie Carl and Giorgio Rattone, who demonstrated the transmissibility of tetanus for the first time. They produced tetanus in rabbits by injecting their sciatic nerve with pus from a fatal human tetanus case in that same year.
In 1889, C. tetani was isolated from a human victim, by Kitasato Shibasaburō
Kitasato Shibasaburō
Baron was a Japanese physician and bacteriologist. He is remembered as the co-discoverer of the infectious agent of bubonic plague in Hong Kong in 1894, almost simultaneously with Alexandre Yersin.-Biography:...

, who later showed that the organism could produce disease when injected into animals, and that the toxin could be neutralized by specific antibodies. In 1897, Edmond Nocard
Edmond Nocard
Edmond Isidore Etienne Nocard , was a French veterinarian and microbiologist, born in Provins ....

 showed that tetanus antitoxin induced passive immunity
Passive immunity
Passive immunity is the transfer of active humoral immunity in the form of readymade antibodies, from one individual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and can also be induced artificially, when high levels...

 in humans, and could be used for prophylaxis and treatment. Tetanus toxoid vaccine
Toxoid
A toxoid is a bacterial toxin whose toxicity has been weakened or suppressed either by chemical or heat treatment, while other properties, typically immunogenicity, are maintained. In international medical literature the preparation also is known as Anatoxin or Anatoxine...

 was developed by P. Descombey in 1924, and was widely used to prevent tetanus induced by battle wounds during World War II.

Characteristics

C. tetani is a rod-shaped, obligate anaerobe which stains Gram positive in fresh cultures; established cultures may stain Gram negative. During vegetative growth, the organism cannot survive in the presence of oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

, is heat-sensitive and exhibits flagellar
Flagellum
A flagellum is a tail-like projection that protrudes from the cell body of certain prokaryotic and eukaryotic cells, and plays the dual role of locomotion and sense organ, being sensitive to chemicals and temperatures outside the cell. There are some notable differences between prokaryotic and...

 motility
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...

. As the bacterium matures, it develops a terminal spore
Endospore
An endospore is a dormant, tough, and temporarily non-reproductive structure produced by certain bacteria from the Firmicute phylum. The name "endospore" is suggestive of a spore or seed-like form , but it is not a true spore . It is a stripped-down, dormant form to which the bacterium can reduce...

, which gives the organism its characteristic appearance. C. tetani spores are extremely hardy as they are resistant to heat and most antiseptics. The spores are distributed widely in manure
Manure
Manure is organic matter used as organic fertilizer in agriculture. Manures contribute to the fertility of the soil by adding organic matter and nutrients, such as nitrogen, that are trapped by bacteria in the soil...

-treated soils and can also be found on human skin and in contaminated heroin.

Vaccination

Tetanus can be prevented through the highly effective tetanus vaccine
Tetanus vaccine
Tetanus vaccine is a vaccine used against Clostridium tetani, the agent that causes tetanus.The vaccine is composed of tetanus toxoid, tetanus toxin inactivated with formaldehyde, which is immunogenic but not pathogenic. It is a component of the DPT vaccine.The tetanus vaccine is required again...

, which is a tetanus toxin inactivated with formaldehyde to be immunogenic but not pathogenic
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

. The vaccine can be formulated as simple or adsorbed Tetanus vaccine, combined Tetanus and Killed Polio vaccine, or the older DTP
DTP
-Computing:* Distributed transaction processing, in computer systems, usually refers to the X/Open model of co-ordinating transactions between multiple participants* Desktop publishing, a technological publishing method * Dynamic Trunking Protocol...

 (diphtheria
Diphtheria
Diphtheria is an upper respiratory tract illness caused by Corynebacterium diphtheriae, a facultative anaerobic, Gram-positive bacterium. It is characterized by sore throat, low fever, and an adherent membrane on the tonsils, pharynx, and/or nasal cavity...

, tetanus, pertussis
Pertussis
Pertussis, also known as whooping cough , is a highly contagious bacterial disease caused by Bordetella pertussis. Symptoms are initially mild, and then develop into severe coughing fits, which produce the namesake high-pitched "whoop" sound in infected babies and children when they inhale air...

) vaccine. Side effects are rare, but if they do occur, include:
  • Fever
    Fever
    Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

  • Pain at the injection site
  • Unexplained crying in infants, irritability in older children or adults.

Severe reactions are extremely rare and include anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...

, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s and encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...

. These events are thought to occur less if only the tetanus-diphtheria component of the vaccine is given. It is recommended that all infants receive the vaccine at 2, 4, 6, and 15 months of age. A fifth booster dose should be given at 4–6 years of age. After that, it should be given every 10 years. However, if a bite, scratch, or puncture occurs more than five years after the last dose of vaccine, the patients should receive another dose of vaccine.

Toxicity

C. tetani usually enters a host through a wound to the skin and then it replicates. Once an infection is established, C. tetani produces two exotoxins, tetanolysin
Tetanolysin
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....

 and tetanospasmin
Tetanospasmin
Tetanus toxin is an extremely potent neurotoxin produced by the vegetative cell of Clostridium tetani 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, tetanospasmin or...

. Eleven strains of C. tetani have been identified, which differ primarily in flagellar antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

s and in their ability to produce tetanospasmin. The genes that produce toxin are encoded on a plasmid
Plasmid
In microbiology and genetics, a plasmid is a DNA molecule that is separate from, and can replicate independently of, the chromosomal DNA. They are double-stranded and, in many cases, circular...

 which is present in all toxigenic strains, and all strains that are capable of producing toxin produce identical toxins.

Tetanolysin serves no known benefit to C. tetani. Tetanospasmin is a neurotoxin
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...

 that causes the clinical manifestations of tetanus. Tetanus toxin is generated in living bacteria, and is released when the bacteria lyse
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....

, such as during spore germination or during vegetative growth. A minimal amount of spore germination and vegetative cell growth are required for toxin production.

On the basis of weight, tetanospasmin is one of the most potent toxins known(based on tests conducted on mice). The estimated minimum human lethal dose is 2.5 nanograms per kilogram of body weight, or 175 nanograms in a 70 kg (154 lb) human. The only toxins more lethal to mice are botulinum toxin
Botulinum toxin
Botulinum toxin is a protein produced by the bacterium Clostridium botulinum, and is considered the most powerful neurotoxin ever discovered. Botulinum toxin causes Botulism poisoning, a serious and life-threatening illness in humans and animals...

, produced by close relative Clostridium botulinum
Clostridium botulinum
Clostridium botulinum is a Gram-positive, rod-shaped bacterium that produces several toxins. The best known are its neurotoxins, subdivided in types A-G, that cause the flaccid muscular paralysis seen in botulism. It is also the main paralytic agent in botox. C. botulinum is an anaerobic...

and the exotoxin
Diphtheria toxin
Diphtheria toxin is an exotoxin secreted by Corynebacterium diphtheriae, the pathogen bacterium that causes diphtheria. Unusually, the toxin gene is encoded by a bacteriophage...

 produced by Corynebacterium diphtheriae
Corynebacterium diphtheriae
Corynebacterium diphtheriae is a pathogenic bacterium that causes diphtheria. It is also known as the Klebs-Löffler bacillus, because it was discovered in 1884 by German bacteriologists Edwin Klebs and Friedrich Löffler .-Classification:Four subspecies are recognized: C. diphtheriae mitis, C....

, the causative agent of diphtheria
Diphtheria
Diphtheria is an upper respiratory tract illness caused by Corynebacterium diphtheriae, a facultative anaerobic, Gram-positive bacterium. It is characterized by sore throat, low fever, and an adherent membrane on the tonsils, pharynx, and/or nasal cavity...

. It should be noted however, that humans and other animals may react differently to specific toxins when compared to mice and that the overall lethality of a specific toxin likely varies between different animals.

Tetanospasmin is a zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

-dependent metalloproteinase
Metalloproteinase
Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...

 that is structurally similar to botulinum toxin but with different effects. C. tetani synthesizes tetanospasmin as a single 150kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...

 polypeptide progenitor toxin that is then cleaved by a protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

 into two fragments; fragment A (a 50kDa "light chain") and fragment B (a 100 kDa "heavy chain") which remain connected via a disulfide bridge
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

. Cleavage of the progenitor toxin into A and B fragments can be induced artificially by trypsin
Trypsin
Trypsin is a serine protease found in the digestive system of many vertebrates, where it hydrolyses proteins. Trypsin is produced in the pancreas as the inactive proenzyme trypsinogen. Trypsin cleaves peptide chains mainly at the carboxyl side of the amino acids lysine or arginine, except when...

.

Toxin Action

Tetanospasmin released in the wound is absorbed into the circulation and reaches ends of motor nerves all over the body. The toxin acts at several sites within the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 including peripheral nerve terminals, the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

, and brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

, and within the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...

. By binding to peripheral motor neuron terminals, the toxin enters the nerve axons, and is transported across synaptic junctions
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

 to the nerve-cell body in the brain stem and spinal cord by retrograde intraneuronal transport, until it reaches the central nervous system, where it rapidly binds to ganglioside
Ganglioside
Ganglioside is a molecule composed of a glycosphingolipid with one or more sialic acids linked on the sugar chain. The 60+ known gangliosides differ mainly in the position and number of NANA residues.It is a component of the cell plasma membrane that modulates cell signal transduction events...

s at the presynaptic junctions of inhibitory motor nerve endings.

The clinical manifestations of tetanus are caused when tetanus toxin blocks inhibitory impulses, by interfering with the release of neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

s, including glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

 and gamma-aminobutyric acid
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...

. These inhibitory neurotransmitters inhibit the alpha motor neuron
Alpha motor neuron
Alpha motor neurons are large lower motor neurons of the brainstem and spinal cord. They innervate extrafusal muscle fibers of skeletal muscle and are directly responsible for initiating their contraction...

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
Risus sardonicus is a highly characteristic, abnormal, sustained spasm of the facial muscles that appears to produce grinning.The name of the condition derives from the appearance of raised eyebrows and an open "grin" - which can appear malevolent to the lay observer - displayed by those suffering...

 (a rigid smile), trismus
Trismus
-Common causes:*Pericoronitis is the most common cause of trismus.*Inflammation of muscles of mastication. It is a frequent sequel to surgical removal of mandibular third molars . The condition is usually resolved on its own in 10–14 days, during which time eating and oral hygiene are compromised...

 (commonly known as "lock-jaw"), and opisthotonus
Opisthotonus
Opisthotonus or opisthotonos, from Greek roots, opistho meaning "behind" and tonos meaning "tension", is a state of a severe hyperextension and spasticity in which an individual's head, neck and spinal column enter into a complete "bridging" or "arching" position...

 (rigid, arched back). Seizures may occur, and the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...

 may also be affected. Tetanospasmin appears to prevent the release of neurotransmitters by selectively cleaving a component of synaptic vesicles called synaptobrevin
Synaptobrevin
Synaptobrevins are small integral membrane proteins of secretory vesicles with molecular weight of 18 kilodalton that are part of the vesicle-associated membrane protein family....

 II. Loss of inhibition also affects preganglionic sympathetic neurons in the lateral gray matter
Gray Matter
"Gray Matter" is a short story by Stephen King, first published in the October 1973 issue of Cavalier magazine, and later collected in King's 1978 collection Night Shift. It is set in the same area as King's novel Dreamcatcher.-Setting:...

 of the spinal cord and produce sympathetic hyperactivity and high circulating catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...

 levels. Hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

 and tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

 alternating with hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

 and bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

may develop.

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