Editing Exotoxin

{{Short description|Toxin from bacteria that destroys or disrupts cells}}
{{More citations needed|date=June 2010}}
[[File:Immune Response to Exotoxins.png|thumb|373x373px|
This figure shows that exotoxins are secreted by bacterial cells, ''Clostridium botulinum'' for example, and are toxic to somatic cells. Somatic cells have [[antibody|antibodies]] on the cell wall to target exotoxins and bind to them, preventing the invasion of somatic cells. The binding of the exotoxin and antibody forms an antigen-antibody interaction and the exotoxins are targeted for destruction by the immune system. If this interaction does not happen, the exotoxins bind to the [[exotoxin receptor]]s that are on the cell surface and causes death of the host cell by inhibiting protein synthesis. This figure also shows that the application of heat or chemicals to exotoxins can result in the deactivation of exotoxins. The deactivated exotoxins are called toxoids and they are not harmful to somatic cells.
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An '''exotoxin''' is a [[toxin]] secreted by [[bacteria]].<ref>{{cite book |editor-last1=Ryan |editor-first1=Kenneth J. |editor-last2=Ray |editor-first2=C. George |title=Sherris medical microbiology |year=2010 |publisher=McGraw Hill Medical |location=New York |isbn=978-0-07-160402-4 |edition=5th}}</ref> 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 [[endotoxin]]s, 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 interaction|host–pathogen interface]].

They may exert their effect locally or produce systemic effects. Well-known exotoxins include: [[botulinum toxin]] produced by ''[[Clostridium botulinum]]''; ''[[Corynebacterium diphtheriae]]'' toxin, produced during life-threatening symptoms of [[diphtheria]]; [[tetanospasmin]] produced by ''[[Clostridium tetani]]''. The toxic properties of most exotoxins can be inactivated by heat or chemical treatment to produce a [[toxoid]]. These retain their antigenic specificity and can be used to produce [[antitoxin]]s and, in the case of diphtheria and tetanus toxoids, are used as vaccines.

Exotoxins are susceptible to [[antibodies]] produced by the [[immune system]], but some exotoxins are so toxic that they may be fatal to the host before the immune system has a chance to mount defenses against them. In such cases, antitoxin, anti-serum containing antibodies, can sometimes be injected to provide [[passive immunity]].

== Types ==

Many exotoxins have been categorized.<ref>{{cite book|title=Desk Encyclopedia of Microbiology |publisher=Elsevier Academic Press |location=Amsterdam |year=2004 |pages=428 |isbn=978-0-12-621361-4 }}</ref><ref name="urlBacterial Pathogenesis: Bacterial Factors that Damage the Host - Producing Exotoxins">{{cite web |url=http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/bacpath/exotox.html |title=Bacterial Pathogenesis: Bacterial Factors that Damage the Host - Producing Exotoxins |access-date=2008-12-13 |url-status=dead |archive-url=https://web.archive.org/web/20100727003355/http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/bacpath/exotox.html |archive-date=2010-07-27 }}</ref> This classification, while fairly exhaustive, is not the only system used. Other systems for classifying or identifying toxins include:

* By organism generating the toxin
* By organism susceptible to the toxin
* By secretion system used to release the toxin (for example, toxic effectors of [[type VI secretion system]])
* By tissue target type susceptible to the toxin ([[neurotoxin]]s affect the nervous system, [[cardiotoxin]]s affect the heart, etc.)
* By structure (for example, [[AB5 toxin]])
* By domain architecture of the toxin (for example, [[polymorphic toxins]])
* By the ability of the toxin to endure in hostile environments, such as heat, dryness, radiation, or salinity. In this context, "labile" implies susceptibility, and "stable" implies a lack of susceptibility.
* By a letter, such as "A", "B", or "C", to communicate the order in which they were identified.

The same exotoxin may have different names, depending on the field of research.

=== Type I: cell surface-active ===

Type I toxins bind to a receptor on the cell surface and stimulate intracellular signaling pathways.  Two examples are described below.

==== Superantigens ====

[[Superantigens]] are produced by several bacteria.  The best-characterized superantigens are those produced by the strains of ''[[Staphylococcus aureus]]'' and ''[[Streptococcus pyogenes]]'' that cause [[toxic shock syndrome]].  Superantigens bridge the [[MHC class II]] protein on [[antigen-presenting cells]] with the [[T-cell receptor]] on the surface of [[T cells]] with a particular Vβ chain. As a consequence, up to 50% of all T cells are activated, leading to massive secretion of proinflammatory [[cytokines]], which produce the symptoms of toxic shock.

==== Heat-stable enterotoxins ====

Some strains of ''[[E. coli]]'' produce [[heat-stable enterotoxin]]s (ST), which are small peptides that are able to withstand heat treatment at 100&nbsp;°C.  Different STs recognize distinct receptors on the cell surface and thereby affect different intracellular signaling pathways.  For example, STa [[enterotoxins]] bind and activate membrane-bound guanylate cyclase, which leads to the intracellular accumulation of [[cyclic GMP]] and downstream effects on several signaling pathways.  These events lead to the loss of electrolytes and water from intestinal cells.

=== Type II: membrane damaging ===

Membrane-damaging toxins exhibit [[hemolysin]] or cytolysin activity ''in vitro''.  However, induction of cell lysis may not be the primary function of the toxins during infection.  At low concentrations of toxin, more subtle effects such as modulation of host cell signal transduction may be observed in the absence of cell lysis. Membrane-damaging toxins can be divided into two categories, the channel-forming toxins and toxins that function as enzymes that act on the membrane.

==== Channel-forming toxins ====

Most [[Pore-forming toxins|channel-forming toxins]], which form pores in the target cell membrane, can be classified into two families: the cholesterol-dependent toxins and the RTX toxins.

* '''Cholesterol-dependent cytolysins'''

Formation of pores by [[cholesterol-dependent cytolysin]]s (CDC) requires the presence of [[cholesterol]] in the target cell.  The size of the pores formed by members of this family is extremely large: 25–30&nbsp;nm in diameter. All CDCs are secreted by the type II [[secretion]] system;<ref name="pmid16177291">{{cite journal | vauthors = Tweten RK | title = Cholesterol-dependent cytolysins, a family of versatile pore-forming toxins | journal = Infection and Immunity | volume = 73 | issue = 10 | pages = 6199–209 | date = October 2005 | pmid = 16177291 | pmc = 1230961 | doi = 10.1128/IAI.73.10.6199-6209.2005 }}</ref> the exception is [[pneumolysin]], which is released from the cytoplasm of ''[[Streptococcus pneumoniae]]'' when the bacteria lyse.

The CDCs ''Streptococcus pneumoniae'' Pneumolysin, ''[[Clostridium perfringens]]'' [[perfringolysin O]], and ''[[Listeria monocytogenes]]'' [[listeriolysin O]] cause specific modifications of [[histone]]s in the host [[cell nucleus]], resulting in down-regulation of several genes that encode proteins involved in the [[inflammatory response]].<ref name="pmid17675409">{{cite journal | vauthors = Hamon MA, Batsché E, Régnault B, Tham TN, Seveau S, Muchardt C, Cossart P | title = Histone modifications induced by a family of bacterial toxins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 33 | pages = 13467–72 | date = August 2007 | pmid = 17675409 | pmc = 1948930 | doi = 10.1073/pnas.0702729104 | bibcode = 2007PNAS..10413467H | doi-access = free }}</ref> Histone modification does not involve the pore-forming activity of the CDCs.

* '''RTX toxins'''

[[RTX toxin]]s can be identified by the presence of a specific tandemly repeated nine-amino acid residue sequence in the protein.  The prototype member of the RTX toxin family is [[haemolysin A]] (HlyA) of ''E. coli''.{{Citation needed|date=March 2009}} RTX is also found in ''[[Legionella pneumophila]]''.<ref name="pmid18194518">{{cite journal | vauthors = D'Auria G, Jiménez N, Peris-Bondia F, Pelaz C, Latorre A, Moya A | title = Virulence factor rtx in Legionella pneumophila, evidence suggesting it is a modular multifunctional protein | journal = BMC Genomics | volume = 9 | pages = 14 | date = January 2008 | pmid = 18194518 | pmc = 2257941 | doi = 10.1186/1471-2164-9-14 | url =  | doi-access = free }}</ref>

==== Enzymatically active toxins ====

One example is the [[Clostridium perfringens alpha toxin|α toxin]] of [[Clostridium perfringens|''C. perfringens'']], which causes [[gas gangrene]]; α toxin has [[phospholipase]] activity.

=== Type III: intracellular ===
Type III exotoxins can be classified by their mode of entry into the cell, or by their mechanism once inside.

==== By mode of entry ====
Intracellular toxins must be able to gain access to the cytoplasm of the target cell to exert their effects.

* Some bacteria deliver toxins directly from their cytoplasm to the cytoplasm of the target cell through a needle-like structure.  The effector proteins injected by the type III [[secretion]] apparatus of ''[[Yersinia]]'' into target cells are one example.
* Another group of intracellular toxins is the [[AB toxin]]s.  The 'B'-subunit ('''''b'''inding'') attaches to target regions on cell membranes, the 'A'-subunit ('''''a'''ctive'') enters through the membrane and possesses [[enzymatic]] function that affects internal cellular bio-mechanisms. A common example of this A-subunit activity is called [[ADP-ribosylation]] in which the A-subunit catalyzes the addition of an ADP-ribose group onto specific residues on a protein.  The structure of these toxins allows for the development of specific [[vaccine]]s and treatments. Certain compounds can be attached to the B unit, which is not, in general, harmful, which the body learns to recognize, and which elicits an [[immunity (medical)|immune response]]. This allows the body to detect the harmful toxin if it is encountered later, and to eliminate it before it can cause harm to the host. Toxins of this type include [[cholera toxin]], [[pertussis toxin]], [[Shiga toxin]] and heat-labile [[enterotoxin]] from ''E. coli''.

==== By mechanism ====

Once in the cell, many of the exotoxins act at the eukaryotic [[ribosome]]s (especially [[60S]]), as [[protein synthesis inhibitor]]s. (Ribosome structure is one of the most important differences between eukaryotes and prokaryotes, and, in a sense, these exotoxins are the bacterial equivalent of antibiotics such as [[clindamycin]].)

* Some exotoxins act directly at the ribosome to inhibit protein synthesis. An example is [[Shiga toxin]].
* Other toxins act at [[elongation factor-2]]. In the case of the [[diphtheria toxin]], EF2 is ADP-ribosylated and becomes unable to participate in protein elongation, and, so, the cell dies. [[Pseudomonas exotoxin]] has a similar action.

Other intracellular toxins do not directly inhibit protein synthesis.
* For example, [[Cholera toxin]] ADP-ribosylates, thereby activating tissue adenylate cyclase to increase the concentration of cAMP, which causes the movement of massive amounts of fluid and electrolytes from the lining of the small intestine and results in life-threatening diarrhea.
* Another example is [[Pertussis toxin]].

=== Extracellular matrix damage ===

These "toxins" allow the further spread of bacteria and, as a consequence, deeper tissue infections.  Examples are [[hyaluronidase]] and [[collagenase]]. These molecules, however, are enzymes that are secreted by a variety of organisms and are not usually considered toxins. They are often referred to as [[virulence factor]]s, since they allow the organisms to move deeper into the hosts tissues.<ref>{{cite book |vauthors=Machunis-Masuoka E, Bauman RW, Tizard IR |title=Microbiology |url=https://archive.org/details/microbiology00baum |url-access=registration |publisher=Pearson/Benjamin Cummings |location=San Francisco |year=2004 |isbn=978-0-8053-7590-9}}</ref>

== Medical applications ==

=== Vaccinations ===
Exotoxins have been used to produce vaccines. This process involves inactivating the toxin, creating a [[toxoid]] that does not induce toxin-related illness and is well tolerated.<ref name=":0">{{cite journal | vauthors = Scott LJ, McCormack PL | title = Reduced-antigen, combined diphtheria, tetanus, and acellular pertussis vaccine, adsorbed (boostrix(®)): a guide to its use as a single-dose booster immunization against pertussis | journal = BioDrugs | volume = 27 | issue = 1 | pages = 75–81 | date = February 2013 | pmid = 23329401 | doi = 10.1007/s40259-012-0009-y | s2cid = 18873223 }}</ref> A widely used toxoid vaccine is the [[DPT vaccine]], which is usually administered in multiple doses throughout childhood with [[adjuvant]]s and [[Booster dose|boosters]] for long-term immunity.<ref name=":0" /> DPT vaccine protects against [[pertussis]], [[tetanus]] and [[diphtheria]] infections, caused by the exotoxin-producing ''[[Bordetella pertussis]]'', ''[[Clostridium tetani]]'' and ''[[Corynebacterium diphtheriae]]'' respectively.<ref name=":3">{{cite journal | vauthors = Zarei S, Jeddi-Tehrani M, Akhondi MM, Zeraati H, Pourheidari F, Ostadkarampour M, Tavangar B, Shokri F | title = Primary immunization with a triple diphtheria-tetanus-whole cell pertussis vaccine in Iranian infants: an analysis of antibody response | journal = Iranian Journal of Allergy, Asthma, and Immunology | volume = 8 | issue = 2 | pages = 85–93 | date = June 2009 | pmid = 19671937 | url = http://ijaai.tums.ac.ir/index.php/ijaai/article/view/239}}</ref> Vaccination with the toxoids generates antibodies against the exotoxins, forming immunological memory as protection against subsequent infections.<ref name=":0" /><ref name=":4">{{cite journal | vauthors = Thierry-Carstensen B, Jordan K, Uhlving HH, Dalby T, Sørensen C, Jensen AM, Heilmann C | title = A randomised, double-blind, non-inferiority clinical trial on the safety and immunogenicity of a tetanus, diphtheria and monocomponent acellular pertussis (TdaP) vaccine in comparison to a tetanus and diphtheria (Td) vaccine when given as booster vaccinations to healthy adults | journal = Vaccine | volume = 30 | issue = 37 | pages = 5464–71 | date = August 2012 | pmid = 22776216 | doi = 10.1016/j.vaccine.2012.06.073 }}</ref> The DPT vaccination may cause adverse side effects, such as swelling, redness and fever, and is contraindicated in some populations.<ref name=":0" /> Effective vaccination schedules have reduced rates of mortality linked to pertussis, tetanus and diphtheria but formal controlled trials to test the efficacy of the vaccine have not been conducted.<ref name=":0" /> Additionally, pertussis persists endemically<ref name=":3" /> and is one of the most common causes of vaccine-preventable deaths.<ref name=":4" />

=== Cancer treatment ===
As exotoxins are highly potent, there has been development in their application to cancer treatment. Cancer cells can be eliminated without destroying normal cells like in chemotherapy or radiation by attaching an antibody or receptor ligand to the exotoxin, creating a [[Immunotoxin|recombinant toxin]] that is targeted to certain cells.<ref name=":1">{{cite journal | vauthors = Kreitman RJ | title = Immunotoxins in cancer therapy | journal = Current Opinion in Immunology | volume = 11 | issue = 5 | pages = 570–8 | date = October 1999 | pmid = 10508704 | doi = 10.1016/s0952-7915(99)00005-9 }}</ref> The cancer cell is killed once the toxin is internalized;<ref name=":1" /> for example, [[Pseudomonas exotoxin]] disrupts protein synthesis after cellular uptake.<ref name=":2">{{cite journal | vauthors = Weldon JE, Pastan I | title = A guide to taming a toxin--recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer | journal = The FEBS Journal | volume = 278 | issue = 23 | pages = 4683–700 | date = December 2011 | pmid = 21585657 | pmc = 3179548 | doi = 10.1111/j.1742-4658.2011.08182.x }}</ref> Multiple versions of recombinant exotoxin A, secreted by ''[[Pseudomonas aeruginosa]]'', have entered clinical trials against tumor growth but have yet to be approved by [[Food and Drug Administration]] (FDA).<ref name=":2" /> A recombinant diphtheria exotoxin has been approved by the FDA for treatment of [[Cutaneous T cell lymphoma|cutaneous T-cell lymphoma]], an immune system cancer.<ref name=":2" /> Further testing to improve clinical efficacy of treatment using recombinant exotoxins continues.<ref name=":1" />

== See also ==
* [[Infectious disease]]
* [[Mycotoxin]]
* [[Membrane vesicle trafficking]]

== References ==
<references />

==External links==
*{{Commonscatinline}}
*{{MeshName|Exotoxins}}

{{Toxins}}

[[Category:Toxins]]
[[Category:Microbiology]]