Microbial toxins aretoxins produced bymicro-organisms, includingbacteria,fungi,protozoa,dinoflagellates, andviruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. Endotoxins most commonly refer to the lipopolysaccharide (LPS) or lipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. Thebotulinum toxin, which is primarily produced byClostridium botulinum and less frequently by otherClostridium species, is the most toxic substance known in the world.[1] However, microbial toxins also have important uses in medical science and research. Currently, new methods of detecting bacterial toxins are being developed to better isolate and understand these toxins. Potential applications of toxin research include combating microbial virulence, the development of novel anticancer drugs and other medicines, and the use of toxins as tools inneurobiology andcellular biology.[2]
Bacteria toxins which can be classified as eitherexotoxins orendotoxins. Exotoxins are generated and actively secreted; endotoxins remain part of the bacteria. Usually, an endotoxin is part of thebacterial outer membrane, and it is not released until the bacterium is killed by theimmune system. The body's response to an endotoxin can involve severeinflammation. In general, the inflammation process is usually considered beneficial to the infected host, but if the reaction is severe enough, it can lead tosepsis. Exotoxins are typically proteins with enzymatic activity that interfere with host cells triggering the symptoms associated with the disease. Exotoxins are also relatively specific to the bacteria that produce it; for example, diphtheria toxin is only produced byCorynebacterium diphtheriae bacteria and is required for the diphtheria disease.[3] Some bacterial toxins can be used in the treatment oftumors.[4] Endotoxins most commonly refer to thelipopolysaccharide (LPS) orlipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. Not all strains of a bacteria species are virulent; there are some strains of Corynebacterium diphtheriae that do not produce diphtheria toxin and are considered nonvirulent and nontoxigenic. Additional classifications used to describe toxins includeenterotoxin,neurotoxin,leukocidin orhemolysin which indicate where in the host's body the toxin targets. Enterotoxins target the intestines, neurotoxins target neurons, leukocidin target leukocytes (white blood cells), and hemolysins target red blood cells. Exotoxin activity can be separated into specific cytotoxic activity or broad cytotoxic activity based on whether the toxin targets specific cell types or various cell types and tissues, respectively. Lethal toxins refers to the group of toxins that are the obvious agents responsible for death associated with the infection.
Toxinosis is pathogenesis caused by the bacterial toxin alone, not necessarily involvingbacterial infection (e.g. when the bacteria have died, but have already produced toxin, which are ingested). It can be caused byStaphylococcus aureus toxins, for example.[5]
There are over 200Clostridium species in the world that live in mundane places such as soil, water, dust, and even our digestive tracts. Some of these species produce harmful toxins such as botulinum toxin and tetanus toxin among others. MostClostridium species that do have toxins typically have AB toxins with part of the toxin involved in cellular entry and the other element delivering a toxic cargo, that is often an enzyme into the cell.[6] Clostridial toxins are widespread and are common causes of disease in humans and other organisms.
Clostridioides difficile
Toxin A andToxin B are the two major toxins produced byClostridioides difficile. Toxin A and toxin B are glucosyltransferases that cause the antibiotic-associated pseudomembranous colitis and severe diarrhea that characterize disease presentation ofClostridioides difficile infections.[7] The binary toxin toxin CDT is also produced by some strains ofC. difficile.[8]
Botulinum neurotoxins (BoNTs) are the causative agents 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 that benefit from its paralytic properties, an example drug with BoNTs as the active ingredient is Botox.[2] TBotulinum neurotoxins (BoNTs) are protein neurotoxins that are produced by the bacteriaClostridium. BoNTs are now largely being studied due to their ability to aid in chronic inflammatory diseases such as acne, multiple sclerosis, and for cosmetic purposes.
Clostridium tetani produces tetanus toxin (TeNT protein), which leads to a fatal condition known astetanus in many vertebrates (including humans).[9] Tetanus toxin is produced fromClostridium tetani, a spore forming bacteria commonly found in soil, Tetanus is a paralytic disease that commonly affects newborns and non-immunized individuals. Tetanus enters the body of organisms through wounds or skin breaks and can be found in manure, soil, and dust. Tetanus mechanism includes tetanus preventing the transmission ofglycine andγ-aminobutyric acid from inhibitoryinterneurons in the spinal cord, leading to activation of motor neurons causing contraction (known as spastic paralysis). It can also cause dysautonomia through a similar process that leads to autonomic dysinhibition. When tetanus toxin enters the body it is taken up bycholinergic nerve endings travel through axons into the spinal cord, the toxin is subsequently released from motor neurons and reuptaken into inhibitory nerve terminals triggering loss of inhibition and exaggerated reflexes in intoxicated individuals. Tetanus intoxication is a vaccine preventable illness.[10]
Clostridium perfringens is ananaerobic,gram-positive bacteria that is often found in the large and small intestines of humans and other animals.Clostridium perfringens has the ability to reproduce quickly producing toxins relating to the cause of diseases. The pore-forming toxin perfringolysin has the ability to causegangrene in calves with the presence of alpha toxin.
Immune evasion proteins fromStaphylococcus 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 andneutrophils. These secreted virulence factors assist the bacterium in surviving immune response mechanisms.[2]
Examples of toxins produced by strains ofS. aureus include enterotoxins that cause food-poisoning, exfoliative toxins that causescalded skin syndrome, andtoxic-shock syndrome toxin (TSST) that underliestoxic shock syndrome.[7] These toxin examples are classified assuperantigens.[7]
Multi-drug resistantS. aureus strains also produce alpha toxin, classified as apore-forming toxin, which can causeabscesses.[7]
Shiga toxins (Stxs), responsible for foodborne illnesses, are a classification of toxins produced byShiga toxin-producingEscherichia coli (STEC) andShigella dysenteriae serotype 1. Stx was first identified inS. dysenteriae and was later found to be produced by certain strains ofE. coli.[11] Stxs act through inhibiting protein synthesis of infected cells and can be divided into two antigenically different groups: Stx/Stx1 and Stx2.[7] Stx1 is immunologically equivalent to Stx; however, it received a separate name to indicate that it is produced by STEC and notS. dysenteriae. Stx2 is produced only by STEC and is antigenically different from Stx/Stx1. The term shiga-like toxins was previously used to further distinguish the shiga toxins produced byE. coli, but nowadays, they are collectively referred to as shiga toxins.[11] Within the STEC strains, a subgroup classified as enterohemorrhagicE. coli (EHEC) represent a class of pathogens with more severe virulence factors in addition to the ability to produce Stxs. EHEC infections result in more severe diseases of hemorrhagic colitis andhemolytic uremic syndrome.[7] There are around 200 strains of STEC, and the wide range of diversity and virulence between them can be partly attributed to phage-mediated horizontal transfer of genetic material.[12]
Anthrax disease in humans results from infection with toxin producingBacillus anthracis strains that can be inhaled, ingested in contaminated food or drink, or obtained through breaks in the skin like cuts or scrapes.[13] Domestic and wild animals can also be infected via inhalation or ingestion. Depending on the route of entry, disease can present initially as inhalation anthrax, cutaneous anthrax, or gastrointestinal anthrax, but eventually will spread throughout the body, resulting in death, if not treated with antibiotics.[13]Anthrax toxin is composed of three domains: protective antigen (PA), edema factor (EF), and lethal factor (LF). EF is an adenylate cyclase that targets ATP. LF enzyme is a metalloprotease that confers the lethal phenotype associated with anthrax disease.[7] As LF is the agent responsible for the death of infected hosts, it is classified in the group of lethal toxins.[3]
Diphtheria toxin is produced by virulentCorynebacterium diphtheriae that infect the mucosal membranes of the throat and nasal cavity causing a gray, thickened lining of the throat, sore throat, weakness, mild fever, swollen glands of the neck, and difficulty breathing.[14] Diphtheria toxin is an ADP-ribosyltransferase that inhibits protein synthesis which causes the symptoms associated with the disease.[7]Diphtheria used to be a leading cause of childhood death until the creation of a vaccine.[14] Thediphtheria vaccine contains a diphtheria toxoid, antigenically identical yet inactivated and non-toxic. When the toxoid is introduced to the body in a vaccine, an immune response is mounted withoutsequelae associated with the toxigenicity.[3]
Pertussis toxin is produced by virulentBordetella pertussis and is responsible for the disease of whooping cough, a respiratory disease that can be fatal for infants. The severe, uncontrollable coughing makes it difficult to breathe causing the "whooping" sound that occurs with inhalation.[15]Bordetella pertussis targets cilia of the upper respiratory tract which are damaged by the pertussis toxin, an ADP-ribosyltransferase that targets G-proteins.[7]
Cholera, characterized by copious watery diarrhea, is a potentially life-threatening illness transmitted through the fecal–oral route via food or water contaminated with toxigenicVibrio cholerae.[16]V. cholerae targets the intestines and secretescholera toxin, an exotoxin and potent enterotoxin that acts as anADP-ribosyltransferase targetingG-proteins.[7] This causes an increase in intracellular cAMP and forces intestinal cells to expel significant amounts of water and electrolytes into the lumen.[17]
Listeriolysin O toxin is an exotoxin produced byListeria monocytogenes and is associated with foodborne systemic illness andmeningitis.[7] Listeriolysin O toxin is classified as a pore-forming toxin that targets host cholesterol cells, inserting a pore into the host cell plasma membrane and permanently disabling cellular functioning.[3]
Lipopolysaccharides (LPS) produced by gram-negative bacteria are an example of endotoxins. LSP are structural components of the bacteria's outer membrane that only become toxic to the host as a result of the immune system's destruction of the bacteria cell membrane.[3]
β-Methylamino-L-alanine (BMAA) is a neurotoxin produced bycyanobacteria that live in the roots ofcycads. BMAA may be present in starch made from the stems and/or seeds of cycads (such asFlorida arrowroot flour) that has not been sufficiently washed, or in meat from animals that have eaten cycads.[18]
The most prominent naturaltoxin groups that exist in aquatic environments aremycotoxins,algal toxins, bacterial toxins, and plant toxins (8). These marine biotoxins are dangerous to human health and have been widely studied due to their high potential to bioaccumulate in edible parts of seafood.[19]
Autotrophicbacteria andalgae are unrelated organisms; however, in aquatic environments, they are bothprimary producers.[20]Cyanobacteria are an important autotrophic bacteria in the water food web. Explosions of cyanobacteria known as algal blooms can producecyanotoxins harmful to both the ecosystem and human health. These harmful algal blooms are more likely to be produced at a dangerous amount when there is an excess ofnutrients, the temperature is 20 °C, there is more light, and calmer waters.[20]Eutrophication and other contamination can lead to an environment that promotescyanobacteria blooms.[20] Processes that promote an excess of nutrients, and human activities, such asagricultural runoff andsewage overflows, are primarily responsible.[19] Other factors include algal species andgrazers being in higher concentrations, allowing for an abundance of cyanobacterial organisms that are associated with the production of toxins.[19] Detection of the extent of an algal bloom begins by taking samples of water at various depths and locations in the bloom.[19]
SPATT was introduced in 2004 as a method of monitoring aquatic toxins. This tool is able to adsorb toxins generated bymicroalgae or cyanobacteria, known ascyanotoxins.[21] The adsorption is passive, and thebiotoxins adhere to porous, resin filled sachets, or SPATT bags where they are then physically removed and examined.[22]
SPATT is a useful tool in tracking algal blooms as it is reliable, sensitive, and inexpensive. It has the ability to quickly alert the existence of aquatic toxins which prevents it from bioaccumulating in marine life.[22] One of the downsides is that it does not give very good results for water-soluble toxins as compared to hydrophobic compounds. This tool is mainly used to determine intercellular concentrations of toxins but the cyanobacteria can also be lysed to determine the total toxin amount in a sample.[19] Other drawbacks, such as a lack in calibration and the ability to only monitor dissolved toxins, make it difficult for this tool to be implemented in a more widespread manner.[21] However, SPATT devices are able to detect manylipophilic and hydrophilic toxins that are linked to harmful algal bloom.[21]
PCR is a molecular tool that allows for analysis of genetic information. PCR is used to amplify the amount of certain DNA within a sample which are usually specific genes within a sample. Genetic targets for cyanobacteria in PCR include the 16S ribosomal RNA gene,phycocyanin operon,internal transcribed spacer region, and theRNA polymerase β subunit gene. PCR is effective when the gene of a known enzyme for producing the microbial toxin or the microbial toxin itself is known.[19] One type of PCR is real time PCR also called quantitative PCR.[23] This type of PCR uses fluorescence and then does an analysis by measuring the amount of fluorescence that reflects the DNA sample more specifically nucleic acids at specific times.[23] Another type of PCR is digital PCR that looks at nucleic acid quantifications. Digital PCR uses dilutions and samples from microlitre reactions to achieve a more accurate quantification of nucleic acids. This type offers a more linear analysis by looking at the positive and negative reactions.[24] Both PCR's are beneficial but there are advantages and disadvantages for both. The digital PCR has several advantages over real time PCR which includes no standard curve, more precise, less affected by simple inhibitors.[25] Digital also has disadvantages to real time which is limited reaction mixture time, more complex and high risk of contamination.[25]
There are many diverse ways of monitoring enzyme levels through the use of enzyme inhibition. The general principle in many of these is the use the knowledge that many enzymes are driven by phosphate-releasing compounds such asadenosine triphosphate. Usingradiolabelled32P phosphate a fluorometric analysis can be used. Or unique polymers can be used to immobilize enzymes and act in an electrochemical biosensor. Overall, the benefits include a fast response time and little sample preparation. Some of the downsides include a lack of specificity in terms of being able to get readings of very small amounts of toxin and the rigidity of the assays in apply certain procedures to different toxins.[19]
This detection method uses mammalian antibodies to bind to microbial toxins which can then be processed in a variety of different ways. Of the commercial ways of using immunochemical detection would beenzyme-linked immunosorbent assays (ELISA). This assay has the advantage of being able to screen for a broad range of toxins but could have issues with specificity depending on the antibody used.[19] A more exotic setup involves the use of CdSquantum dots which are used in an electro-chemiluminescent immunosensor.[26] A major aspect of immunochemical methods being tested in laboratories are uses ofnanowires and other nanomaterials to detect microbial toxins.[19]
These toxins are produced byVibrio species of bacteria and like to accumulate in marine life such as the pufferfish. These toxins are produced whenVibrio bacteria are stressed by changes in temperature and salinity of environment which leads towards production of toxins. The main hazard towards humans is during consumption of contaminated seafood.Tetrodotoxin poisoning is becoming common in more northern and typically colder marine waters as higher precipitation and warmer waters from climate change triggersVibrio bacteria to produce toxins.[7] Most of the marine life that produce this toxin are typically found in warm water, for example the Red Sea and the Mediterranean Sea.[27] For example, pufferfish do produce this toxin, some pufferfish, such as Takifugu V., produce tetrodotoxin in their skin glands.[28] Another organism that releases the tetrodotoxin from their skin areblue-ringed octopuses (Hapalochlaena fasciata). TheNatica lineata snails produce the tetrodotoxin and store it in the muscle. The snail releases the toxin by absorbing water into the muscle cavity and it is released when the snail is attacked.[29] Once a human consumes the toxin, the individual could experience mild symptoms such asparesthesias of the lips or tongue, vomiting and headaches. The individual could also experience severe symptoms such as respiratory or heart failure. At this time there is no treatment for tetrodotoxin poisoning other than respiratory support.[30]
There is only one viral toxin that has been described so far:NSP4 fromrotavirus. It inhibits themicrotubule-mediated secretory pathway and alterscytoskeleton organization in polarizedepithelial cells. It has been identified as the viralenterotoxin based on the observation that the protein caused diarrhea when administered intraperitoneally or intra-ileally in infant mice in an age-dependent manner.[31] NSP4 can induce aqueous secretion in the gastrointestinal tract of neonatal mice through activation of an age- andCa2+
-dependent plasma membrane anion permeability.[32]
Severalbacteriophages contain toxin genes that become incorporated into the host bacteria genome through infection and render the bacteria toxic.[12] Many well known bacterial toxins are produced from specific strains of the bacteria species that have obtained toxigenicity throughlysogenic conversion, pseudolysogeny, orhorizontal gene transfer.[12] Although these are not viral toxins, researchers remain extremely interested in the role phages play bacterial toxins due to their contribution to pathogenesis (toxigenesis), virulence, transmissibility and general evolution of bacteria.[12] Examples of toxins encoded by phage genes:
Some mycoviruses also contain toxin genes expressed by host fungal species upon viral infection.[37] While these toxins are classified as mycotoxins, the role of mycoviruses is also of interest to researchers in terms of fungal virulence.[37] Examples include the mycoviruses ScV-M1, ScV-M2, and ScV-M28 in theTotiviridae family that contain "killer toxin" genes K1, K2, and K3, respectively.[37] These "killer toxins" are produced by yeast, namely of theSaccharomyces cerevisiae species, that destroy neighboring yeast cells.[37] Recently, researchers discovered that it is only the yeasts infected with either ScV-M1, ScV-M2, or ScV-M28 mycoviruses that have the ability to produce a "killer toxin".[37]
Mycotoxins aresecondary metabolites that are constructed bymicrofungi.[38] Mycotoxins can be harmful because they can cause disease and death in humans and animals.[38] They are found in many pharmaceuticals like antibiotics and growth developments.[38] Mycotoxins can also play a role inchemical warfare agents (CWA), which are chemicals that contain toxins that are used to cause death, harm, or injuries to individuals that are considered enemies by the military during warfare.[39]
Mycotoxins are synthesized by different types of moulds and are built by a wide group of toxins.[40] Mycotoxins have a low molecular weight compound that is usually less than 1000 grams per mol.[40] There are roughly 400 toxic mycotoxins that are constructed by 100 different fungi species that have been researched.[40] Mycotoxins gain access into the body of a human or animal by food, they can contaminate many different types of agriculture during cultivation, harvesting, storage, and areas with high humidity.[40] TheFood and Agriculture Organization reported that about 25% of products produced by agriculture contain mycotoxins and this can lead to economic losses in the agricultural community.[40] Levels of mycotoxin secretion can rely on varying temperatures, the ideal temperature for mycotoxins to grow is from 20 degrees Celsius to 37 degrees Celsius.[40] Mycotoxin production also relies heavily on water activity, the ideal range would be from 0.83 to 0.9 aw and higher.[40] Humidity plays a key in the production of mycotoxins as well.[40] Higher levels of humidity (between 70% and 90%) and moisture (between 20% and 25%) allow mycotoxins to grow more rapidly.[40] Foods that mycotoxins are found in cereal, spices, and seeds.[40] They can also be found in eggs, milk, and meat from animals that have been contaminated during their feeding process.[40] Since they are resistant to high temperatures and physical and chemical reception, it is considered unavoidable while cooking at high temperatures.[40]
Trichothecene is a mycotoxin that is produced from the fungi speciesFusarium graminearum.[41] TheT-2 toxin, Type A, and DON, Type B, are major mycotoxins that are responsible for toxicity in humans and animals.[41] These two types come from anepoxide at the C12 and C13 positions in the trichothecenes.[41] The T-2 toxin was found after civilians ate wheat that was contaminated by theFusarium fungi during WWII from a biological weapon. The T-2 toxin was an outbreak and made humans develop symptoms likefood poisoning, chills, nausea, dizziness, etc.[41] The trichothecenes mycotoxin affects animals by decreasing plasma glucose, red blood cell andleukocyte counts.[41] Pathological changes in the liver and stomach, as well as weight loss has been accounted for.[41]
Zearalenone is a mycotoxin that is produced fromFusarium graminearum andFusarium culmorum that are found in different types of foods and feeds.[41] Zearalenone is anon-steroidal estrogenic mycotoxin that is found in farm animal's reproductive disorders and in humans it causes hypoestrogenic syndrome.[41] Effects that come from zearalenone includeenlarged uterus, improperly running reproductive tract, decreasing the fertility in women, and causesprogesterone andestradiol levels to become abnormal.[41] If zearalenone is consumed during pregnancy, it can cause reduced fetal weight and decrease the chance of survival for the embryo.[41]
Fumonisins,Fusarium verticillioides, are found in nature wherefumonisin B1 has largely contaminated the area.[41] These mycotoxins are hydrophilic compounds. Studies have shown that esophageal cancer can be related back to corn grain that contains fumonisins.[41] Other effects from fumonisins are birth defects of the brain, spine, and spinal cord.[41] In animals, problems with the pulmonary edema andhydrothorax swines have been proven to have association with fumonisins.[41]
Ochratoxin is a mycotoxin that is produced byAspergillus species andPenicillium species.[41] The most researched ochratoxin is theochratoxin A (OTA), which is a fungal toxin.[41] This mycotoxin targets the OTA of kidneys and causes kidney disease in humans.[41] Ochratoxin A is animmunosuppressive compound.[41] Ochratoxin is a renal carcinogen, which has been found by animals containing OTA.[41]
Aflatoxin is a mycotoxin that is produced fromAspergillus flavus andAspergillus parasiticus.[41] A type of aflatoxin,AFB1, is the most common mycotoxin that is found in human food and animal feed.[41] AFB1 targets the liver of both humans and animals.[41] Acute aflatoxicosis can make humans and animals have symptoms like abdominal pain, vomiting, and even death.[41]
Botulinum toxins, exotoxins of Clostridium botulinum, are the most toxic naturally occurring substances known to man.
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