Microbial toxins

Microbial toxins are toxins produced by microorganisms, including bacteria, viruses and fungi. Microbial toxins are important virulence determinants responsible for microbial pathogenicity and/or evasion of the host immune response. Some bacterial toxins, such as Botulinum neurotoxins, are the most potent natural toxins known. However, microbial toxins also have important uses in medical science and research. Potential applications of toxin research include combating microbial virulence, the development of novel anti-cancer drugs and other medicines, and the use of toxins as tools in neurobiology and cellular biology.^[1]'

Botulinum neurotoxin

Botulinum neurotoxins (BoNTs) are the most potent natural toxins known. The family of BoNTs comprises seven antigenically distinct serotypes (A to G) that are produced by various toxigenic strains of spore-forming anaerobic Clostridium botulinum. They act as metalloproteinases that enter peripheral cholinergic nerve terminals and cleave proteins that are crucial components of the neuroexocytosis apparatus, causing a persistent but reversible inhibition of neurotransmitter release resulting in flaccid muscle paralysis. They are the causative agent of the deadly food poisoning disease, botulism, and could pose a major biological warfare threat due to their extreme toxicity and ease of production. They also serve as powerful tools to treat an ever expanding list of medical conditions.^[2]

Tetanus toxin

Clostridium tetani produces tetanus toxin (TeNT protein) which leads to a fatal condition known as tetanus in many vertebrates (including humans) and invertebrates.

Anthrax toxin

Bacillus anthracis produces two major virulence factors, a tripartite exotoxin referred to as anthrax toxin, and an antiphagocytic capsule. These virulence factors mediate pathogen survival and, in the case of toxin, directly induce damage to the host. Two distinct enzymatic activities are associated with anthrax toxin, each encoded by a separate protein. The enzymatic subunits are lethal factor (LF), a zinc-dependent metalloproteinase, and oedema factor (EF), a calcium- and calmodulin-dependent adenylate cyclase. LF and EF gain access to the host cytosol by binding to and translocating through a pore formed by the shared binding subunit, protective antigen (PA). The combination of LF and PA is called lethal toxin (LT), and this toxin inactivates MAPK/ERK pathway in the host. Edema toxin (ET), formed by the combination of EF and PA, produces high cAMP levels in host cells. Early during infection, systemic toxin levels are low, and likely modulate the host immune response locally, thereby allowing for establishment of infection. Late in infection, toxin concentrations increase causing organ damage, vascular leakage, and ultimately death of the host.^[3]

Subtilase cytotoxin

Subtilase cytotoxin (SubAB) is the recently-recognised prototype of a new AB5 toxin family secreted by Shiga toxigenic Escherichia coli (STEC). Its A subunit is a subtilase-like serine protease and cytotoxicity for eukaryotic cells is due to a highly specific, single-site cleavage of BiP/GRP78, an essential Hsp70 family chaperone located in the ER. This cleavage triggers a severe ER stress response, ultimately resulting in apoptosis. The B subunit has specificity for glycans terminating in the sialic acid N-glycolylneuraminic acid. The role of SubAB in human disease remains to be established.^[4]

Pasteurella multocida toxin

Pasteurella multocida toxin (PMT) is the major pathogenic deteriment of Pasteurella multocida. The species P. multocida causes various diseases of animals and humans. The toxin is the causative agent of the economically important atrophic rhinitis in swine. Stimulation of several signalling pathways is induced by PMT. Most remarkable is a potent mitogenic effect. Phospholipase Cβ and the small GTPase Rho are activated due to stimulation of heterotrimeric G proteins of the Gαq and Gα12/13 family.^[5]

Vibrio RTX toxins

Multifunctional-Autoprocessing RTX toxins are a unique family of secreted proteins toxins, predominantly produced by the Vibrio sp. The best characterized of these toxins is produced by V. cholerae. In the eukaryotic cell, this toxin has three distinct biochemical activities resulting in autoprocessing, covalent crosslinking of actin, and inactivation of Rho-family GTPases, ultimately resulting in destruction of the actin cytoskeleton. Related toxins produced by V. vulnificus and V. anguillarum have some similar mechanisms of action. These toxins may assist the bacterium to evade host immune defenses.^[6]

Helicobacter pylori toxin

Helicobacter pylori, a Gram-negative bacterium that colonizes the human stomach, secretes a toxin known as VacA. This toxin was initially identified based on its ability to cause vacuolation in cultured gastric epithelial cells. VacA causes several other alterations in gastric epithelial cells and targets multiple types of immune cells. Most VacA-induced cellular alterations are attributable to insertion of the toxin into cellular membranes and the formation of membrane channels.^[7]

Staphylococcal toxins

Immune evasion proteins from Staphylococcus aureus have a significant conservation of protein structures and a range of activities that are all directed at the two key elements of host immunity, complement and neutrophils. These secreted virulence factors assist the bacterium in surviving immune response mechanisms.^[8]

Cyanobacteria toxins

Main article: Cyanotoxin

Cyanobacteria produce a large variety of bioactive compounds, including substances with anti-cancer and anti-viral activity, UV protectants, specific inhibitors of enzymes, and potent hepatotoxins and neurotoxins.^[9]

Mycotoxins

In agriculture, Aspergillus originally was considered a serious problem largely because of its prevalence in the biodeterioration of stored crops and as an opportunistic pathogen of field crops, particularly under high moisture conditions. During the early 1960s, the discovery of aflatoxins associated with massive deaths of poultry, trout and other domesticated animals species worldwide raised new awareness that these fungi posed threats to foods and feeds beyond their ability to rot plant materials. Research on aflatoxins led to a so-called 'golden age' of mycotoxin research during which many new fungal toxins were discovered from species of Aspergillus and other common moulds. In addition to aflatoxins, other important Aspergillus mycotoxins include ochratoxin, patulin and fumigillin.^[1][10]

Aflatoxins are still recognized as the most important mycotoxins. They are synthesized by only a few Aspergillus species of which A. flavus and A. parasiticus are the most problematic. The expression of aflatoxin-related diseases is influenced by factors such as age, nutrition, sex, species and the possibility of concurrent exposure to other toxins. The main target organ in mammals is the liver so aflatoxicosis is primarily a hepatic disease. Conditions increasing the likelihood of aflatoxicosis in humans include limited availability of food, environmental conditions that favour mould growth on foodstuffs, and lack of regulatory systems for aflatoxin monitoring and control.^[10]

A. flavus and A. parasiticus are weedy moulds that grow on a large number of substrates, particularly under high moisture conditions. Aflatoxins have been isolated from all major cereal crops, and from sources as diverse as peanut butter and marijuana. The staple commodities regularly contaminated with aflatoxins include cassava, chillies, corn, cotton seed, millet, peanuts, rice, sorghum, sunflower seeds, tree nuts, wheat, and a variety of spices intended for human or animal food use. When processed, aflatoxins get into the general food supply where they have been found in both pet and human foods as well as in feedstocks for agricultural animals. Aflatoxin transformation products are sometimes found in eggs, milk products and meat when animals are fed contaminated grains.^[11]

Human exposure to aflatoxins is difficult to avoid because A. flavus grows aggressively in many foods at all stages of the food chain: in the field, in storage and in the home. Evidence for acute human aflatoxicosis has been reported from several underdeveloped countries such as India and Thailand. The symptoms of severe aflatoxicosis include oedema, hemorrhagic necrosis of the liver and profound lethargy. Further, aflatoxins are potent carcinogens, especially aflatoxin B1. Based on epidemiological studies done in Asian and Africa, in 1988 the International Agency for Research on Cancer, part of the World Health Organization, placed aflatoxin B1 on the list of human carcinogens. In developed countries, the emphasis on keeping aflatoxin out of the food chain concerns its carcinogenic potential. Strong regulatory limits (4-30 ppb) have been established for many commodities.^[12]

Fungal ribotoxins

Ribotoxins are a family of fungal extracellular ribonucleases which inactivate ribosomes by specifically cleaving a single phosphodiester bond located at the universally conserved sarcin/ricin loop of the large rRNA. The subsequent inhibition of protein biosynthesis is followed by cell death via apoptosis. Ribotoxins are also able to interact with membranes containing acid phospholipids, their cytotoxicity being preferentially directed towards cells showing altered membrane permeability, e.g. transformed or virus infected cells.^[13]

See also

• Alpha toxin
• Anthrax toxin
• Bacterial toxin
• Botulinum toxin
• Cholera toxin
• Cyanotoxin
• Diphtheria toxin
• Exotoxin
• Food microbiology
• Microbiology
• Neurotoxin
• Pertussis toxin
• Shiga toxin
• Shiga-like toxin
• Toxin
• Toxin-antitoxin system

References

1. ^ ^{a b} Proft T (editor) (2009). Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
2. ^ Kukreja R and Singh BR (2009). "Botulinum Neurotoxins: Structure and Mechanism of Action". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
3. ^ Maldonado-Arocho et al. (2009). "Anthrax Toxin". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
4. ^ Paton AW and Paton JC (2009). "Subtilase Cytotoxin". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
5. ^ Orth JHC (2009). "Pasteurella multocida Toxin". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
6. ^ Satchell KJF and Geissler B (2009). "The Multifunctional-Autoprocessing RTX toxins of Vibrios". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
7. ^ Cover TL and Atherton JC (2009). "Helicobacter pylori VacA Toxin". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
8. ^ Langley et al. (2009). "Staphylococcal Immune Evasion Toxins". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
9. ^ Herrero A and Flores E (editor). (2008). The Cyanobacteria: Molecular Biology, Genomics and Evolution. Caister Academic Press. ISBN 978-1-904455-15-8. 
10. ^ ^{a b} Machida, M; Gomi, K (editors) (2010). Aspergillus: Molecular Biology and Genomics. Caister Academic Press. ISBN 978-1-904455-53-0. 
11. ^ Fratamico, PM et al. (editors) (2008). Foodborne Pathogens: Microbiology and Molecular Biology. Horizon Scientific Press. ISBN 978-1-898486-52-7. 
12. ^ Bennett JW (2010). "An Overview of the Genus Aspergillus". Aspergillus: Molecular Biology and Genomics. Caister Academic Press. ISBN 978-1-904455-53-0. http://www.open-access-biology.com/aspergillus/aspergillusch1.pdf. 
13. ^ Herrero-Galan et al. (2009). "Fungal Ribotoxins: Structure, Function and Evolution". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8.