User:Cjbutler14526/Clostridium botulinum

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Clostridium botulinum is a gram-positive, rod-shaped, anaerobic, spore-forming, motile bacterium with the ability to produce the neurotoxin botulinum.

C. botulinum is a diverse group of pathogenic bacteria. Initially, they were grouped together by their ability to produce botulinum toxin and are now known as four distinct groups, C. botulinum groups I–IV, as well as some strains of Clostridium butyricum and Clostridium baratii, are the bacteria responsible for producing botulinum toxin.

The botulinum toxin can cause botulism, a severe flaccid paralytic disease in humans and other animals, and is the most potent toxin known to science, natural or synthetic, with a lethal dose of 1.3–2.1 ng/kg in humans.

C. botulinum is commonly associated with bulging canned food; bulging, misshapen cans can be due to an internal increase in pressure caused by gas produced by bacteria.

C. botulinum is responsible for foodborne botulism (ingestion of preformed toxin), infant botulism (intestinal infection with toxin-forming C. botulinum), and wound botulism (infection of a wound with C. botulinum). C. botulinum produces heat-resistant endospores that are commonly found in soil and are able to survive under adverse conditions.

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Taxonomic history
C. botulinum was first recognized and isolated in 1895 by Emile van Ermengem from home-cured ham implicated in a botulism outbreak. The isolate was originally named Bacillus botulinus, after the Latin word for sausage, botulus. ("Sausage poisoning" was a common problem in 18th- and 19th-century Germany, and was most likely caused by botulism.) However, isolates from subsequent outbreaks were always found to be anaerobic spore formers, so Ida A. Bengtson proposed that both be placed into the genus Clostridium, as the genus Bacillus was restricted to aerobic spore-forming rods.

Since 1959, all species producing the botulinum neurotoxins (types A–G) have been designated C. botulinum. Substantial phenotypic and genotypic evidence exists to demonstrate heterogeneity within the species, with at least four clearly-defined "groups" (see § Groups) straddling other species, implying that they each deserve to be a genospecies.

The situation as of 2018 is as follows:


 * C. botulinum type G (= group IV) strains are since 1988 their own species, C. argentinense.
 * Group I C. botulinum strains that do not produce a botulin toxin are referred to as C. sporogenes. Both names are conserved names since 1999. Group I also contains C. combesii.
 * All other botulinum toxin-producing bacteria, not otherwise classified as C. baratii or C. butyricum, is called C. botulinum. This group still contains three genogroups.

Smith et al. (2018) argues that group I should be called C. parabotulinum and group III be called C. novyi sensu lato, leaving only group II in C. botulinum. This argument is not accepted by the LPSN and would cause an unjustified change of the type strain under the Prokaryotic Code. Dobritsa et al. (2018) argues, without formal descriptions, that group II can potentially be made into two new species.

The complete genome of C. botulinum ATCC 3502 was sequenced at Wellcome Trust Sanger Institute in 2007. This strain encodes a type "A" toxin. The complete genome is composed of one chromosome with 3,886,916 bp and one plasmid with 16,344 bp.

Microbiology
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C. botulinum is a Gram-positive, rod-shaped, spore-forming bacterium. It is an obligate anaerobe, the organism survives in an environment that lacks oxygen. However, C. botulinum tolerates traces of oxygen due to the enzyme superoxide dismutase, which is an important antioxidant defense in nearly all cells exposed to oxygen. C. botulinum is able to produce the neurotoxin only during sporulation, which can happen only in an anaerobic environment.

C. botulinum is divided into four distinct phenotypic groups (I-IV) and is also classified into seven serotypes (A–G) based on the antigenicity of the botulinum toxin produced. On the level visible to DNA sequences, the phenotypic grouping matches the results of whole-genome and rRNA analyses, and setotype grouping approximates the result of analyses focused specifically on the toxin sequence. The two phylogenetic trees do not match because of the ability of the toxin gene cluster to be horizontally transferred

Serotypes
Botulinum neurotoxin (BoNT) production is the unifying feature of the species. Seven serotypes of toxins have been identified that are allocated a letter (A–G), several of which can cause disease in humans. They are resistant to degradation by enzymes found in the gastrointestinal tract. This allows for ingested toxins to be absorbed from the intestines into the bloodstream.Toxins can be further differentiated into subtypes on the bases of smaller variations. However, all types of botulinum toxin are rapidly destroyed by heating to 100 °C for 15 minutes (900 seconds). 80 °C for 30 minutes also destroys BoNT.

Most strains produce one type of BoNT, but strains producing multiple toxins have been described. C. botulinum producing B and F toxin types have been isolated from human botulism cases in New Mexico and California. The toxin type has been designated Bf as the type B toxin was found in excess to the type F. Similarly, strains producing Ab and Af toxins have been reported.

Evidence indicates the neurotoxin genes have been the subject of horizontal gene transfer, possibly from a viral (bacteriophage) source. This theory is supported by the presence of integration sites flanking the toxin in some strains of C. botulinum. However, these integrations sites are degraded (except for the C and D types), indicating that the C. botulinum acquired the toxin genes quite far in the evolutionary past. Nevertheless, further transfers still happen via the plasmids and other mobile elements the genes are located on.

Toxin types in disease
Only botulinum toxin types A, B, E, F and H (FA) cause disease in humans. Types A, B, and E are associated with food-borne illness, while type E is specifically associated with fish products. Type C produces limber-neck in birds and type D causes botulism in other mammals. No disease is associated with type G. The "gold standard" for determining toxin type is a mouse bioassay, but the genes for types A, B, E, and F can now be readily differentiated using quantitative PCR. Type "H" is in fact a recombinant toxin from types A and F. It can be neutralized by type A antitoxin and no longer is considered a distinct type.

The ability of C. botulinum to naturally transfer neurotoxin genes to other clostridia is concerning, especially in the food industry, where preservation systems are designed to destroy or inhibit only C. botulinum but not other Clostridium species.

Metabolism
A large number of the genes on C. botulinum are responsible for the breakdown of essential carbohydrates and metabolism of important sugars. Chitin, for example, is the preferred source of carbon and nitrogen for C. botulinum. Hall A strain of C. botulinum possesses an active chitinolytic system to aid in the breakdown of chitin. However, there is an insignificant amount of research published about the metabolic activity of C. botulinum. Type A and B of C. botulinum production of BoNT is affected by nitrogen and carbon nutrition. There is also evidence that these processes are also under catabolite repression.

Transmission and Sporulation
C. botulinum cannot spread from person to person. Instead C. botulinum will rely on the use of spores and sporulation in order to spread the toxin. The exact mechanism behind sporulation of C. botulinum is not yet known, but there is evidence that shows depending on the strain, sporulation strategies can differ. Different strains of C. botulinum can be divided into three different groups, group I, II, and III, based on environmental conditions like heat resistance, temperature, and biome. It is also evident that within each group, different strains will use different strategies to adapt to their environment in order to survive.

Unlike other Clostridial species, C. botulinum spores will sporulate as it enters the stationary phase. C. botulinum relies on quorum-sensing to initiation the sporulation process.

C. botulinum spores are not found in human feces unless the individual has contracted botulism.

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Motility structures
The most common motility structure for C. botulinum is a flagellum. Though this structure is not found in all strains of C. botulinum, majority produce a peritrichous flagella. When comparing the different strains, there is also differences in the length of the flagellum and how many are present on the cell.

Pathology
=== Foodborne botulism === Signs and symptoms of foodborne botulism typically begin between 18 and 36 hours after the toxin enters your body, but can range from a few hours to several days, depending on the amount of toxin ingested. Symptoms include:


 * Double vision
 * Blurred vision
 * Drooping eyelids (ptosis)
 * Nausea, vomiting, and abdominal cramps
 * Slurred speech
 * Trouble breathing
 * Difficulty in swallowing
 * Dry mouth
 * Muscle weakness
 * Constipation
 * Reduced or absent deep tendon reactions, such as in the knee

=== Wound botulism === Most people who develop wound botulism inject drugs several times a day, so it is difficult to determine how long it takes for signs and symptoms to develop after the toxin enters the body. Most common in people who inject black tar heroin, wound botulism signs and symptoms include:


 * Difficulty swallowing or speaking
 * Facial weakness on both sides of the face
 * Blurred or double vision
 * ptosis
 * Trouble breathing
 * Paralysis

Infant botulism
If infant botulism is related to food, such as honey, problems generally begin within 18 to 36 hours after the toxin enters the baby's body. Signs and symptoms include:


 * Constipation (often the first sign)
 * Floppy movements due to muscle weakness and trouble controlling the head
 * Weak cry
 * Irritability
 * Drooling
 * ptosis
 * Tiredness
 * Difficulty sucking or feeding
 * Paralysis

=== Beneficial effects of botulinum toxin === Purified botulinum toxin is diluted by a physician for treatment of:


 * Congenital pelvic tilt
 * Spasmodic dysphasia (the inability of the muscles of the larynx)
 * Achalasia (esophageal stricture)
 * Strabismus (crossed eyes)
 * Paralysis of the facial muscles
 * Failure of the cervix
 * Blinking frequently
 * Anti-cancer drug delivery

=== Adult intestinal toxemia === A very rare form of botulism that occurs by the same route as infant botulism but is among adults. Occurs rarely and sporadically. Signs and symptoms include:


 * Abdominal pain
 * Blurred vision
 * Diarrhea
 * Dysarthria
 * Imbalance
 * Weakness in arms and hand area

C. botulinum in different geographical locations
A number of quantitative surveys for C. botulinum spores in the environment have suggested a prevalence of specific toxin types in given geographic areas, which remain unexplained.

Botulinum toxin produced by C. botulinum is often believed to be a potential bioweapon as it is so potent that it takes about 75 nanograms to kill a person (LD50 of 1 ng/kg, assuming an average person weighs ~75 kg); 1 kilogram of it would be enough to kill the entire human population.

A "mouse protection" or "mouse bioassay" test determines the type of C. botulinum toxin present using monoclonal antibodies. An enzyme-linked immunosorbent assay (ELISA) with digoxigenin-labeled antibodies can also be used to detect the toxin, and quantitative PCR can detect the toxin genes in the organism.

Growth conditions and prevention
Botulism poisoning can occur due to preserved or home-canned, low-acid food that was not processed using correct preservation times and/or pressure. Growth of the bacterium can be prevented by high acidity, high ratio of dissolved sugar, high levels of oxygen, very low levels of moisture, or storage at temperatures below 3 °C (38 °F) for type A. For example, in a low-acid, canned vegetable such as green beans that are not heated enough to kill the spores (i.e., a pressurized environment) may provide an oxygen-free medium for the spores to grow and produce the toxin. However, pickles are sufficiently acidic to prevent growth; even if the spores are present, they pose no danger to the consumer.

The control of food-borne botulism caused by C. botulinum is based almost entirely on thermal destruction (heating) of the spores or inhibiting spore germination into bacteria and allowing cells to grow and produce toxins in foods. Conditions conducive of growth are dependent on various environmental factors. Growth of C. botulinum is a risk in low acid foods as defined by having a pH above 4.6 although growth is significantly retarded for pH below 4.9. copied from Clostridium botulinum

Honey, corn syrup, and other sweeteners may contain spores, but the spores cannot grow in a highly concentrated sugar solution; however, when a sweetener is diluted in the low-oxygen, low-acid digestive system of an infant, the spores can grow and produce toxin. As soon as infants begin eating solid food, the digestive juices become too acidic for the bacterium to grow.

The control of food-borne botulism caused by C. botulinum is based almost entirely on thermal destruction (heating) of the spores or inhibiting spore germination into bacteria and allowing cells to grow and produce toxins in foods. Conditions conducive of growth are dependent on various environmental factors. Growth of C. botulinum is a risk in low acid foods as defined by having a pH above 4.6 although growth is significantly retarded for pH below 4.9.

In the beginning of 21st century there have been some cases and specific conditions reported to sustain growth with pH below 4.6. but at higher temperature.

Diagnosis
Physicians may consider the diagnosis of botulism based on a patient's clinical presentation, which classically includes an acute onset of bilateral cranial neuropathies and symmetric descending weakness. Other key features of botulism include an absence of fever, symmetric neurologic deficits, normal or slow heart rate and normal blood pressure, and no sensory deficits except for blurred vision. A careful history and physical examination is paramount in order to diagnose the type of botulism, as well as to rule out other conditions with similar findings, such as Guillain–Barré syndrome, stroke, and myasthenia gravis. Depending on the type of botulism considered, different tests for diagnosis may be indicated.

To find how this bacterium becomes a toxin, mice were used in a bioassay to identify toxin levels. Researchers injected the toxin into the mice and waited 48 hours for paralysis to set in, then researchers recorded the time it took for the toxin to cause paralysis. This was recorded to note different types of toxins' ability to cause paralysis.
 * Foodborne botulism: serum analysis for toxins by bioassay in mice should be done, as the demonstration of the toxins is diagnostic.
 * Wound botulism: isolation of C. botulinum from the wound site should be attempted, as growth of the bacteria is diagnostic.
 * Adult enteric and infant botulism: isolation and growth of C. botulinum from stool samples is diagnostic. Infant botulism is a diagnosis which is often missed in the emergency room.

Treatment
In the case of a diagnosis or suspicion of botulism, patients should be hospitalized immediately, even if the diagnosis and/or tests are pending. If botulism is suspected, patients should be treated immediately with antitoxin therapy in order to reduce mortality. Immediate intubation is also highly recommended, as respiratory failure is the primary cause of death from botulism.

In North America, an equine-derived heptavalent botulinum antitoxin is used to treat all serotypes of non-infant naturally occurring botulism. For infants less than one year of age, botulism immune globulin is used to treat type A or type B.

Outcomes vary between one and three months, but with prompt interventions, mortality from botulism ranges from less than 5 percent to 8 percent.

Vaccination
There used to be a formalin-treated toxoid vaccine against botulism (serotypes A-E), but it was discontinued in 2011 due to declining potency in the toxoid stock. It was originally intended for people at risk of exposure. A few new vaccines are under development.