An exotoxin is a toxin A toxin is a poisonous substance produced by living cells or organisms (although humans are technically living organisms, man-made substances created by artificial processes usually are not considered toxins by this definition). It was the organic chemist Ludwig Brieger (1849-1919) who first used the term 'toxin' excreted by a microorganism A microorganism or microbe is an organism that is microscopic (too small to be seen by the naked human eye). The study of microorganisms is called microbiology, a subject that began with Anton van Leeuwenhoek's discovery of microorganisms in 1675, using a microscope of his own design, including bacteria The bacteria ( [bækˈtɪəriə] ; singular: bacterium)[α] are a large group of single-celled, prokaryote microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals. Bacteria are ubiquitous in every habitat on Earth, growing in soil, acidic hot springs, radioactive waste,, fungi A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. The Fungi (pronounced /ˈfʌndʒaɪ/ or /ˈfʌŋɡaɪ/) are classified as a kingdom that is separate from plants, animals and bacteria. One major difference is that fungal cells have cell, algae Algae are a large and diverse group of simple, typically autotrophic organisms, ranging from unicellular to multicellular forms. The largest and most complex marine forms are called seaweeds. They are photosynthetic, like plants, and "simple" because they lack the many distinct organs found in land plants, and protozoa Protozoa is a subkingdom of microorganisms that are classified generally as unicellular non-fungal eukaryotes. Protozoans are a major component of the ecosystem.[1][clarification needed] An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism Metabolism is the set of chemical reactions that happen in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter, for example to harvest energy in cellular. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins Endotoxins are toxins associated with certain bacteria [clarification needed]. Classically, an "endotoxin" is a toxin that, unlike an "exotoxin", is secreted only when the cell is lysed or during bacterial cell division, may be released during 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 is a protein produced by the bacterium Clostridium botulinum, and is known to be highly neurotoxic. When introduced intravenously in monkeys, type A of the toxin exhibits an LD50 of 40-56 ng, type C1 around 32 ng, type D 3200 ng, and type E 88 ng, rendering the above types some of the most powerful neurotoxins known. Despite the produced by Clostridium botulinum Clostridium botulinum is a Gram-positive, rod shaped bacterium that produces the neurotoxin botulin, which causes flaccid muscular paralysis seen in botulism, and is also the main paralytic agent in botox. It is an anaerobic spore-former, which produces oval, subterminal endospores and is commonly found in soil and the Corynebacterium diphtheriae exotoxin which is produced during life threatening symptoms of diphtheria Diphtheria (Greek διφθερα —“pair of leather scrolls") is an upper respiratory tract illness characterized by sore throat, low fever, and an adherent membrane (a pseudomembrane) on the tonsils, pharynx, and/or nasal cavity. A milder form of diphtheria can be restricted to the skin. Uncommon consequences include myocarditis (about 20%.
Exotoxins are susceptible to antibodies Antibodies are gamma globulin proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. They are typically made of basic structural units—each with two large heavy chains and two small light chains—to form, for example, produced by the 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 healthy cells and tissues in order to function, 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.
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Types
Many exotoxins have been categorized by their mode of action on target cells.[2][3]
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 (neurotoxins 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. Bungarotoxin, which is considered a neurotoxin, has its effect at the motor end plate affect the nervous system, cardiotoxins Cardiotoxicity is the occurrence of heart muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood. Cardiotoxicity may be caused by chemotherapy treatment, complications from anorexia nervosa, or an incorrectly administered drug such as Bupivacaine affect the heart, etc.)
- By structure (for example, 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)
- 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 Superantigens are a class of antigens which cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs can be produced by pathogenic microbes (including viruses, mycoplasma, and bacteria) as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response are produced by several bacteria. The best characterized superantigens are those produced by the strains of Staphylococcus aureus Staphylococcus aureus is the most common cause of staph infections. It is a spherical bacterium, frequently part of the skin flora found in the nose and on skin. About 20% of the population are long-term carriers of S. aureus. S. aureus can cause a range of illnesses from minor skin infections, such as pimples, impetigo (may also be caused by and Streptococcus pyogenes Streptococcus pyogenes is a spherical gram-positive bacterium that grows in long chains and is the cause of Group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S. pyogenes typically produces large zones of beta-hemolysis when cultured on blood agar plates and are therefore also called Group A ( that cause toxic shock syndrome Toxic shock syndrome is a very rare but 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. Streptococcal TSS is sometimes referred to as Toxic shock-like syndrome (TSLS). Superantigens bridge the 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 (APCs) protein on antigen presenting cells with the T cell receptor The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is, in general, responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of T cells T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors (TCR). The abbreviation T, in T with a particular Vβ chain. Consequently, up to 20% of all T cells are activated, leading to massive secretion of proinflammatory cytokines Cytokines are any of a number of small proteins that are secreted by specific cells of the immune system and glial cells, which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins, peptides, or glycoproteins, which produce the symptoms of toxic shock.
Heat-stable enterotoxins
Some strains of E. coli Escherichia coli is a Gram negative rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms (endotherms). Most E. coli strains are harmless, but some, such as serotype O157:H7, can cause serious food poisoning in humans, and are occasionally responsible for product recalls. The harmless strains are part of the produce heat-stable enterotoxins (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 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 cytolysins (CDC) such as the α toxin of Staphylococcus aureus Staphylococcus aureus is the most common cause of staph infections. It is a spherical bacterium, frequently part of the skin flora found in the nose and on skin. About 20% of the population are long-term carriers of S. aureus. S. aureus can cause a range of illnesses from minor skin infections, such as pimples, impetigo (may also be caused by requires the presence of cholesterol Cholesterol is a waxy steroid metabolite found in the cell membranes and transported in the blood plasma of all animals. It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture of bile 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 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.[4] The exception is pneumolysin, which is released from the cytoplasm of Streptococcus pneumoniae Streptococcus pneumoniae, or pneumococcus, is gram-positive, alpha-hemolytic, bile soluble aerotolerant anaerobe and a member of the genus Streptococcus. A significant human pathogenic bacterium, S. pneumoniae was recognized as a major cause of pneumonia in the late 19th century and is the subject of many humoral immunity studies when the bacteria lyse. Pneumolysin, Clostridium perfringens Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ubiquitous in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates, insects, and soil perfringolysin, and Listeria monocytogenes listeriolysin O cause specific modifications of histones In biology, histones are strongly alkaline proteins found in eukaryotic cell nuclei, which package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, act as spools around which DNA winds, and play a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very in the host cell nucleus In cell biology, the nucleus , also sometimes referred to as the "control center", 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, resulting in down-regulation of several genes encoding proteins involved in the inflammatory response.[5] Histone modification does not involve the pore-forming activity of the CDCs.
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.[citation needed] RTX is also found in Legionella pneumophila.[6]
Enzymatically Active Toxins
One example is the α toxin of C. perfringens, which causes gas gangrene Gas gangrene is a bacterial infection that produces gas within tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium bacteria. It is a medical emergency. α toxin has 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 what type of reaction they catalyze: 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 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 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 causative agent of the plague. Rodents are the natural into target cells are one example.
- Another group of intracellular toxins is the AB toxins. The 'B'-subunit (binding) attaches to target regions on cell membranes, the 'A'-subunit (active) enters through the membrane and possesses enzymatic Enzymes are biomolecules that catalyze chemical reactions. Nearly all known enzymes are proteins. However, certain RNA molecules can be effective biocatalysts too. These RNA molecules have come to be known as ribozymes. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into 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 vaccines Vaccines can be prophylactic , or therapeutic (e.g. vaccines against cancer are also being investigated; see cancer vaccine) and treatments. Certain compounds can be attached to the B unit, which is not generally harmful, which the body learns to recognize, and which elicits an immune response 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 range of pathogens irrespective of antigenic. 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 is a protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the harmful effects of cholera infection, pertussis 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 sources for Shiga toxin are the bacteria S and heat-stable enterotoxin An enterotoxin is a protein toxin released by a microorganism in the intestine from E. coli.
By mechanism
Once in the cell, many of the exotoxins act at the eukaryotic ribosomes Ribosomes are the components of cells that make proteins from amino acids. One of the central tenets of biology, often referred to as the "central dogma," is that DNA is used to make RNA, which, in turn, is used to make protein. The DNA sequence in genes is copied into a messenger RNA . Ribosomes then read the information in this RNA and (especially 60S The 60s decade ran from January 1, 60, to December 31, 69. It was the seventh decade in the Anno Domini/Common Era, if the nine-year period from 1 AD to 9 AD is considered as a "decade"), as protein synthesis inhibitors. (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 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. It is a common topical treatment for acne and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections.)
- Some exotoxins act directly at the ribosome to inhibit protein synthesis. An example is 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 sources for Shiga toxin are the bacteria S.
- Other toxins act at elongation factor-2. In the case of the diphtheria toxin Diphtheria toxin is an exotoxin secreted by Corynebacterium diphtheriae, the pathogen bacterium that causes diphtheria, 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 don't directly inhibit protein synthesis.
- For example, Cholera toxin Cholera toxin is a protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the harmful effects of cholera infection ADP-ribosylates and thereby activates 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 consequently deeper tissue infections. Examples are hyaluronidase The hyaluronidases are a family of enzymes that degrade hyaluronic acid 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.[7]
See also
References
- ^ exotoxin at Dorland's Medical Dictionary
- ^ Lederberg, Joshua; Schaechter, Moselio (2004). The desk encyclopedia of microbiology. Amsterdam: Elsevier Academic Press. pp. 428. ISBN 0-12-621361-5.
- ^ "Bacterial Pathogenesis: Bacterial Factors that Damage the Host - Producing Exotoxins". http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/bacpath/exotox.html. Retrieved 2008-12-13.
- ^ Tweten RK (2005). "Cholesterol-dependent cytolysins, a family of versatile pore-forming toxins". Infect. Immun. 73 (10): 6199–209. doi:10.1128/IAI.73.10.6199-6209.2005. PMID 16177291.
- ^ Hamon MA, Batsché E, Régnault B, et al. (2007). "Histone modifications induced by a family of bacterial toxins". Proc. Natl. Acad. Sci. U.S.A. 104 (33): 13467–72. doi:10.1073/pnas.0702729104. PMID 17675409.
- ^ D'Auria G, Jiménez N, Peris-Bondia F, Pelaz C, Latorre A, Moya A (2008). "Virulence factor rtx in Legionella pneumophila, evidence suggesting it is a modular multifunctional protein". BMC Genomics 9: 14. doi:10.1186/1471-2164-9-14. PMID 18194518. PMC 2257941. http://www.biomedcentral.com/1471-2164/9/14.
- ^ Machunis-Masuoka E, Bauman RW, Tizard IR (2004). Microbiology. San Francisco: Pearson/Benjamin Cummings. ISBN 0-8053-7590-2.
External links
Categories: Toxins | Bacteriology | Microbiology
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