Exotoxin
Encyclopedia
An exotoxin is a toxin
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...

 excreted by a microorganism
Microorganism
A microorganism or microbe is a microscopic organism that comprises either a single cell , cell clusters, or no cell at all...

, like bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, fungi, algae
Algae
Algae are a large and diverse group of simple, typically autotrophic organisms, ranging from unicellular to multicellular forms, such as the giant kelps that grow to 65 meters in length. They are photosynthetic like plants, and "simple" because their tissues are not organized into the many...

, and protozoa
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...

. 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
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...

s, may be released during lysis
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"....

 of the cell.

Most exotoxins can be destroyed by heating. They may exert their effect locally or produce systemic effects. Well-known exotoxins include the 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 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 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....

exotoxin, which is produced during life-threatening symptoms 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...

.

Exotoxins are susceptible to antibodies produced by the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

, but many exotoxins are so toxic that they may be fatal to the host before the immune system has a chance to mount defenses against it.

Types

Many exotoxins have been categorized

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 tissue target type susceptible to the toxin (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...

    s affect the nervous system, cardiotoxins affect the heart, etc.)
  • By structure (for example, AB5 toxin
    AB5 toxin
    The AB5 toxins are six-component protein complexes secreted by a number of pathogenic bacteria. All share a similar structure and mechanism for entering targeted host cells.- Structure and mechanism :...

    )
  • 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 of 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
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...

and Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...

that cause toxic shock syndrome
Toxic shock syndrome
Toxic shock syndrome is a potentially fatal illness caused by a bacterial toxin. Different bacterial toxins may cause toxic shock syndrome, depending on the situation. The causative bacteria include Staphylococcus aureus and Streptococcus pyogenes...

. Superantigens bridge the MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....

 protein on antigen-presenting cells with the T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...

 on the surface of T cells with a particular Vβ chain. As a consequence, up to 20% 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
Heat-stable enterotoxin
Heat-stable enterotoxins are secretory peptides produced by some bacterial strains, such as enterotoxigenic Escherichia coli which are in general toxic to animals.These peptides keep their 3D structure and remain active at temperatures as high as 100oC....

s (ST), which are small peptides that are able to withstand heat treatment at 100oC. 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
Hemolysin
Hemolysins are exotoxins produced by bacteria that cause lysis of red blood cells in vitro. Visualization of hemolysis of red blood cells in agar plates facilitates the categorization of some pathogenic bacteria such as Streptococcus and Staphylococcus...

 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 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
Cholesterol-dependent cytolysin
Cholesterol-Dependent Cytolysins are a family of β-barrel pore-forming exotoxins that are secreted by Gram-positive bacteria. CDC are secreted as water-soluble monomers of 50-70 kDa, that once bound to the target cell, will form a circular homo-oligomeric complex containing up to 50 monomers...

s (CDC) such as perfringolysin O of Clostridium perfringens
Clostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...

requires the presence of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

 in the target cell. The size of the pores formed by members of this family is extremely large: 25-30 nm in diameter. A conserved 11-amino acid sequence is found at the C-terminus of all family members. Moreover, all CDCs are secreted by the type II secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...

 system. The exception is pneumolysin
Pneumolysin
Pneumolysin is a putative virulence factor of the gram positive bacteria Streptococcus pneumoniae.It is a 53 kDa pore forming toxin composed of 471 amino acids...

, which is released from the cytoplasm of Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...

when the bacteria lyse. Pneumolysin, Clostridium perfringens
Clostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...

perfringolysin, and Listeria monocytogenes listeriolysin O cause specific modifications of histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...

s in the host cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

, resulting in down-regulation of several genes encoding proteins involved in the inflammatory response. Histone modification does not involve the pore-forming activity of the CDCs.
  • RTX toxin
    RTX toxin
    The RTX toxin family is a group of exotoxins produced by gram-negative bacteria. All RTX toxins share a common gene organization and structural appearance. Gram-negative bacteria secrete the toxins into the extracellular space using the type I secretion system. RTX is an abbreviation of "repeats...

    s


RTX (repeats in toxin) cytolysins can be identified by the presence of a specific tandemly-repeated nine-amino acid residue sequence in the protein. The prototype RTX member is the HlyA hemolysin of E. coli. RTX is also found in Legionella pneumophila
Legionella pneumophila
Legionella pneumophila is a thin, ærobic, pleomorphic, flagellated, non-spore forming, Gram-negative bacterium of the genus Legionella. L. pneumophila is the primary human pathogenic bacterium in this group and is the causative agent of legionellosis or Legionnaires' disease.-Characterization:L...

.

Enzymatically Active Toxins

One example is the α toxin of C. perfringens, which causes gas gangrene
Gas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....

; α toxin has phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...

 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
    Secretion
    Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...

     apparatus of Yersinia
    Yersinia
    Yersinia is a genus of bacteria in the family Enterobacteriaceae. Yersinia are Gram-negative rod shaped bacteria, a few micrometers long and fractions of a micrometer in diameter, and are facultative anaerobes. Some members of Yersinia are pathogenic in humans; in particular, Y. pestis is the...

    into target cells are one example.

  • Another group of intracellular toxins is the AB toxin
    AB toxin
    The AB toxins are two-component protein complexes secreted by a number of pathogenic bacteria. They can be classified as Type III toxins because they interfere with internal cell function. They are named AB toxins due to their components: the "A" component is usually the "active" portion, and the...

    s. The 'B'-subunit (binding) attaches to target regions on cell membranes, the 'A'-subunit (active) 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
    ADP-ribosylation
    ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. These reactions are involved in cell signaling and the control of many cell processes, including DNA repair and apoptosis.-ADP-ribosylation enzymes:...

     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
    Vaccine
    A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

    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 immune response
    Immunity (medical)
    Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

    . 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
    Cholera toxin
    Cholera toxin is a protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection.- Structure :...

    , pertussis toxin
    Pertussis toxin
    Pertussis toxin is a protein-based AB5-type exotoxin produced by the bacterium Bordetella pertussis, which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection...

    , Shiga toxin
    Shiga toxin
    Shiga toxins are a family of related toxins with two major groups, Stx1 and Stx2, whose genes are considered to be part of the genome of lambdoid prophages. The toxins are named for Kiyoshi Shiga, who first described the bacterial origin of dysentery caused by Shigella dysenteriae. The most common...

     and heat-liable enterotoxin
    Enterotoxin
    An enterotoxin is a protein toxin released by a microorganism in the intestine. Enterotoxins are chromosomally encoded exotoxins that are produced and secreted from several bacterial organisms. They are often heat-stable, and are of low molecular weight and water-soluble...

     from E. coli.

By mechanism

Once in the cell, many of the exotoxins act at the eukaryotic ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

s (especially 60S
60S
60S is the large ribosomal subunit in eukaryotes. It corresponds to 50S in prokaryotes.It consists of the following:* 5S* 28S* 5.8SThe following is a list of proteins contained within the 60S ribosome:...

), as protein synthesis inhibitor
Protein synthesis inhibitor
A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins....

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
Clindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...

.)
  • Some exotoxins act directly at the ribosome to inhibit protein synthesis. An example is Shiga toxin
    Shiga toxin
    Shiga toxins are a family of related toxins with two major groups, Stx1 and Stx2, whose genes are considered to be part of the genome of lambdoid prophages. The toxins are named for Kiyoshi Shiga, who first described the bacterial origin of dysentery caused by Shigella dysenteriae. The most common...

    .

  • Other toxins act at elongation factor-2. In the case of the diphtheria toxin
    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...

    , EF2 is ADP-ribosylated and becomes unable to participate in protein elongation, and, so, the cell dies. Pseudomonas exotoxin
    Pseudomonas exotoxin
    The Pseudomonas exotoxin is an exotoxin produced by Pseudomonas aeruginosa.It inhibits elongation factor-2. It does so by ADP-ribosylation of EF2. This then causes the elongation of polypeptides to cease.It has been investigated as a treatment for hepatitis B....

     has a similar action.


Other intracellular toxins do not directly inhibit protein synthesis.
  • For example, Cholera toxin
    Cholera toxin
    Cholera toxin is a protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection.- Structure :...

     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
    Pertussis toxin
    Pertussis toxin is a protein-based AB5-type exotoxin produced by the bacterium Bordetella pertussis, which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection...

    .

Extracellular matrix damage

These "toxins" allow the further spread of bacteria and, as a consequence, deeper tissue infections. Examples are hyaluronidase
Hyaluronidase
The hyaluronidases are a family of enzymes that degrade hyaluronic acid.In humans, there are six associated genes, including HYAL1, HYAL2, HYAL3, and PH-20/SPAM1.-Use as a drug:...

 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 factors, since they allow the organisms to move deeper into the hosts tissues.
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