Cytotoxin K

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Cytotoxin K
Cytotoxin K structure.png
The predicted structure of cytotoxin K
Identifiers
Organism Bacillus cereus
SymbolCytK
UniProt Q9EVA1
Search for
Structures Swiss-model
Domains InterPro

Cytotoxin-K (CytK) is a protein toxin produced by the gram-positive bacteria Bacillus cereus . It was first discovered in a certain Bacillus cereus strain which was isolated from a food poisoning epidemic that occurred in a French nursing home in 1998. There were six cases of bloody diarrhea, three of which were fatal. [1] None of the known enterotoxins from B. cereus could be detected at this time. Later, this B. cereus strain and its relatives were classified as a brand-new species called Bacillus cytotoxicus, which is the thermo-tolerant member of the B. cereus genus. [2] The cytotoxin-K gene is present in approximately 50% of Bacillus cereus isolates, and its expression is regulated by several factors, including temperature and nutrient availability.

Contents

Further studies showed that Cytotoxin-K is a pore-forming toxin that can create small holes in cell membranes, leading to cell death. It has been shown to cause damage to intestinal epithelial cells, indicating its potential role in the pathogenesis of Bacillus cereus infections in humans. The toxicity in humans has not been studied in detail but CC50 values of 500-1000nM dTHP-1 cells. In addition, CytK has been shown to have hemolytic activity, meaning it can damage red blood cells. [1]

In addition to its role in Bacillus cereus pathogenesis, Cytotoxin-K has also been studied for its potential as a diagnostic tool for detecting Bacillus cereus contamination in food products. PCR methods have been analyzed that can detect the presence of CytK in food samples, showing CytK detection could be used for rapid and sensitive detection of potentially contaminated products. [3]

Overall, the discovery and characterization of CytK have led to a greater understanding of the virulence factors of Bacillus cereus and have provided insights into potential targets for detecting, preventing and treating Bacillus cereus infections in humans. [2]

Available forms

The Cytotoxin-K gene encodes the Cytotoxin-K toxin. It was initially suggested during the early studies that cytK is not very common among various B. cereus isolates. Further research revealed two distinct cytK gene variants with substantial sequence homology; these were designated cytK-1 and cytK-2 in accordance with their discovery. Studies showed that 89% of the amino acids in the sequences of the related toxins CytK-1 and CytK-2 are identical. [1]

The variations between the proteins CytK-1 and CytK-2 were centered in specific areas of the proteins. When CytK-1 was first analyzed, it was discovered that the toxin was very harmful to human intestinal epithelial cells and that it was hemolytic, dermo necrotic and that it was capable of creating pores in lipid layers. [1] Although their toxicity was only around 20% that of CytK-1, the isolated CytK-2 proteins likewise demonstrated hemolysis and toxicity towards human intestinal Caco-2 cells and Vero cells. The B. cereus CytK-2 proteins, both native and recombinant, were capable of forming pores in planar lipid bilayers, although the majority of the channels they produced had lower conductance than those made by CytK-1. Although not all CytK-2 toxins may be as dangerous as the first discovered CytK-1, it is likely that CytK-2 toxins contribute to the enterotoxicity of some strains of B. cereus. [4]

The production of Cytotoxin-K is important for the pathogenesis of Bacillus cereus, as it plays a role in the disruption of host cell membranes, allowing the bacterium to invade and colonize host tissues. [1] Understanding the different forms of CytK is important for developing effective strategies to control the spread of Bacillus cereus and prevent foodborn illness.

Structure

Cytotoxin K is a protein with a size of 34 kDa. The X-ray structure of this protein has not yet been determined but genetic analysis has elucidated some things about the structure. The CytK-2 gene is more studied but did not show any similarity with other genes which encode for enterotoxins produced by the bacteria B. cereus. It did show a similar sequence for a putative histidine kinase site and this can act as an recognition site for PlcR. [5] PlcR does regulate the transcription of other known enterotoxins produced by this bacteria like HBL and Nhe [5] which lead to believe that also CytK-2 does have a similar disease pattern like HBL and Nhe even if the sequence of the gene itself does not show this directly [5]

The amino acid sequence of CytK-2 does actually show 30% similarity with α-hemolysin of S. aureus which lead to believe that CytK-2 falls in the same group of β-barrel channel-forming toxins [6] which may explain the idea that CytK plays a role in a similar disease pattern as HBL and Nhe. The glycine-rich part of CytK, which aligns the most with the stem region of α-hemolysin (64%) and may adopt a similar structure.

This α-hemolysin of S. aureus synthesis which really does have much similarities with CytK-2 depends on different pairs of histidine kinases and response regulators, it is therefore tempting to suggest the possibility that a two-component system with a histidine kinase and a response regulator is also involved in regulation of the transcription of CytK, in addition to PlcR' at least on behalf of and on behalf of [5] who showed this recognition site in the promotor region of CytK-2.

Mechanism of toxicity

cytotoxin K forms pores in the outer membrane CytotoxinK.png
cytotoxin K forms pores in the outer membrane

Cytotoxin-K (CytK) is excreted via de Sec translocation pathway. [7] and has shown to be hemolytic dermonecrotic and highly toxic towards human epithelial cells by inducing pyroptosis. [7] [8] Cytotoxin K induces this inflammatory cell death by interacting with phosphatidic acid (PA) and to a lesser extent PtdIns(4)P, PtdIns(4,5)P2, and PtdIns(3,4,5)P3 which are membrane lipids. [8] By binding to the cellular membrane and oligomerization of cytotoxin K the protein forms pores that have a predicted opening size of 7 Armstrong. [1] These pores cause changes the integrity of the membrane. As a result of this potassium ions efflux out of the cells while calcium ions accumulate disrupting the cellular homeostasis. [8] The change in intercellular ion concentrations results in the activation of NLRP3. [8] NLRP3 activation results in the formation of the inflammasome which in turn activates Gasdermin D and interleukin 1B. [8] Gasdermin D then forms pores in the membrane and releases the interleukins and causes swelling and eventually bursting of the cell. [9] The pore forming mechanisms of the two variants CytK1 and CytK2 haven't been fully investigated but are deducted from close protein families such as S. aureus α- and γ-hemolysin, C. perfringens β-toxin, and B. cereus hemolysin II which share significant homology. [1] Thus, CytK is classified as member of the family of β-barrel pore-forming toxins [1]

Indications

CytK toxin is produced by certain strains of Bacillus cereus, a type of bacteria commonly found in soil, water, and food. Like other toxins produced by this bacteria, such as HBL and Nhe, consuming CytK toxin can cause diarrhea and other gastrointestinal symptoms (9).

If you suspect that you may have consumed CytK toxin, here are some indications to look out for:

If you experience any of these symptoms after eating food contaminated with CytK toxin, seek medical attention immediately if after 24 hours the symptoms did not diminish, there are some cases of really worse seizures due to the intoxication (10). It's important to stay hydrated by drinking plenty of fluids, especially water or oral rehydration solutions, to replace lost fluids and electrolytes.

Related Research Articles

<i>Bacillus cereus</i> Species of bacterium

Bacillus cereus is a Gram-positive rod-shaped bacterium commonly found in soil, food, and marine sponges. The specific name, cereus, meaning "waxy" in Latin, refers to the appearance of colonies grown on blood agar. Some strains are harmful to humans and cause foodborne illness due to their spore-forming nature, while other strains can be beneficial as probiotics for animals, and even exhibit mutualism with certain plants. B. cereus bacteria may be anaerobes or facultative anaerobes, and like other members of the genus Bacillus, can produce protective endospores. They have a wide range of virulence factors, including phospholipase C, cereulide, sphingomyelinase, metalloproteases, and cytotoxin K, many of which are regulated via quorum sensing. B. cereus strains exhibit flagellar motility.

<span class="mw-page-title-main">Shiga toxin</span> Family of related toxins

Shiga toxins are a family of related toxins with two major groups, Stx1 and Stx2, expressed by genes considered to be part of the genome of lambdoid prophages. The toxins are named after Kiyoshi Shiga, who first described the bacterial origin of dysentery caused by Shigella dysenteriae. Shiga-like toxin (SLT) is a historical term for similar or identical toxins produced by Escherichia coli. The most common sources for Shiga toxin are the bacteria S. dysenteriae and some serotypes of Escherichia coli (STEC), which includes serotypes O157:H7, and O104:H4.

<i>Bacillus thuringiensis israelensis</i> Subspecies of bacterium

Bacillus thuringiensis serotype israelensis (Bti) is a group of bacteria used as biological control agents for larvae stages of certain dipterans. Bti produces toxins which are effective in killing various species of mosquitoes, fungus gnats, and blackflies, while having almost no effect on other organisms. The major advantage of B. thuringiensis products is that they are thought to affect few non-target species. However, even though Bti may have minimal direct effects on non-target organisms, it may potentially be associated with knock-on effects on food webs and other ecosystem properties, including biodiversity and ecosystem functioning.

<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. 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 endotoxins, 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 interface.

<span class="mw-page-title-main">Enterotoxin</span> Toxin from a microorganism affecting the intestines

An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines. They can be chromosomally or plasmid encoded. They are heat labile (>60⁰), of low molecular weight and water-soluble. Enterotoxins are frequently cytotoxic and kill cells by altering the apical membrane permeability of the mucosal (epithelial) cells of the intestinal wall. They are mostly pore-forming toxins, secreted by bacteria, that assemble to form pores in cell membranes. This causes the cells to die.

Cytolysin refers to the substance secreted by microorganisms, plants or animals that is specifically toxic to individual cells, in many cases causing their dissolution through lysis. Cytolysins that have a specific action for certain cells are named accordingly. For instance, the cytolysins responsible for the destruction of red blood cells, thereby liberating hemoglobins, are named hemolysins, and so on. Cytolysins may be involved in immunity as well as in venoms.

<span class="mw-page-title-main">Pore-forming toxin</span> Protein-produced toxins that create pores in cell membrane

Pore-forming proteins are usually produced by bacteria, and include a number of protein exotoxins but may also be produced by other organisms such as apple snails that produce perivitellin-2 or earthworms, who produce lysenin. They are frequently cytotoxic, as they create unregulated pores in the membrane of targeted cells.

The AB5 toxins are six-component protein complexes secreted by certain pathogenic bacteria known to cause human diseases such as cholera, dysentery, and hemolytic–uremic syndrome. One component is known as the A subunit, and the remaining five components are B subunits. All of these toxins share a similar structure and mechanism for entering targeted host cells. The B subunit is responsible for binding to receptors to open up a pathway for the A subunit to enter the cell. The A subunit is then able to use its catalytic machinery to take over the host cell's regular functions.

<span class="mw-page-title-main">Hemolysin</span> Molecule destroying the membrane of red blood cells

Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acquisition, many hemolysins produced by pathogens do not cause significant destruction of red blood cells during infection. However, hemolysins are often capable of lysing red blood cells in vitro.

<span class="mw-page-title-main">Delta endotoxin</span> Group of insecticidal toxins produced by the bacteria Bacillus thuringiensis

Delta endotoxins (δ-endotoxins) are pore-forming toxins produced by Bacillus thuringiensis species of bacteria. They are useful for their insecticidal action and are the primary toxin produced by Bt maize/corn. During spore formation the bacteria produce crystals of such proteins that are also known as parasporal bodies, next to the endospores; as a result some members are known as a parasporin. The Cyt (cytolytic) toxin group is a group of delta-endotoxins different from the Cry group.

<i>Bacillus anthracis</i> Species of bacterium

Bacillus anthracis is a gram-positive and rod-shaped bacterium that causes anthrax, a deadly disease to livestock and, occasionally, to humans. It is the only permanent (obligate) pathogen within the genus Bacillus. Its infection is a type of zoonosis, as it is transmitted from animals to humans. It was discovered by a German physician Robert Koch in 1876, and became the first bacterium to be experimentally shown as a pathogen. The discovery was also the first scientific evidence for the germ theory of diseases.

'Staphylococcus aureus delta toxin is a toxin produced by Staphylococcus aureus. It has a wide spectrum of cytolytic activity.

<span class="mw-page-title-main">Clostridium difficile toxin B</span>

Clostridium difficile toxin B is a cytotoxin produced by the bacteria Clostridioides difficile, formerly known as Clostridium difficile. It is one of two major kinds of toxins produced by C. difficile, the other being a related enterotoxin. Both are very potent and lethal.

<span class="mw-page-title-main">Clostridium difficile toxin A</span>

Clostridium difficile toxin A (TcdA) is a toxin generated by Clostridioides difficile, formerly known as Clostridium difficile. It is similar to Clostridium difficile Toxin B. The toxins are the main virulence factors produced by the gram positive, anaerobic, Clostridioides difficile bacteria. The toxins function by damaging the intestinal mucosa and cause the symptoms of C. difficile infection, including pseudomembranous colitis.

Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. 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. The botulinum toxin, which is primarily produced by Clostridium botulinum and less frequently by other Clostridium species, is the most toxic substance known in the world. 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 in neurobiology and cellular biology.

The RTX toxin superfamily is a group of cytolysins and cytotoxins produced by bacteria. There are over 1000 known members with a variety of functions. The RTX family is defined by two common features: characteristic repeats in the toxin protein sequences, and extracellular secretion by the type I secretion systems (T1SS). The name RTX refers to the glycine and aspartate-rich repeats located at the C-terminus of the toxin proteins, which facilitate export by a dedicated T1SS encoded within the rtx operon.

In molecular biology, the Bacillus haemolytic enterotoxin family of proteins consists of several Bacillus haemolytic enterotoxins, which can cause food poisoning in humans. Haemolysin BL and non-haemolytic enterotoxin, represent the major enterotoxins produced by Bacillus cereus. Most of the cytotoxic activity of B. cereus isolates has been attributed to the level of Nhe, which may indicate a highly diarrheic potential. The exact mechanism by which B. cereus causes diarrhoea is unknown. Hbl, cytotoxin K (CytK) and Nhe are all putative causes.

The Clostridial Cytotoxin (CCT) Family is a member of the RTX-toxin superfamily. There are currently 13 classified members belonging to the CCT family. A representative list of these proteins is available in the Transporter Classification Database. Homologues are found in a variety of Gram-positive and Gram-negative bacteria.

<span class="mw-page-title-main">GSDMD</span> Protein found in humans

Gasdermin D (GSDMD) is a protein that in humans is encoded by the GSDMD gene on chromosome 8. It belongs to the gasdermin family which is conserved among vertebrates and comprises six members in humans, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and DFNB59 (Pejvakin). Members of the gasdermin family are expressed in a variety of cell types including epithelial cells and immune cells. GSDMA, GSDMB, GSDMC, GSDMD and GSDME have been suggested to act as tumour suppressors.

<span class="mw-page-title-main">Cry6Aa</span>

Cry6Aa is a toxic crystal protein generated by the bacterial family Bacillus thuringiensis during sporulation. This protein is a member of the alpha pore forming toxins family, which gives it insecticidal qualities advantageous in agricultural pest control. Each Cry protein has some level of target specificity; Cry6Aa has specific toxic action against coleopteran insects and nematodes. The corresponding B. thuringiensis gene, cry6aa, is located on bacterial plasmids. Along with several other Cry protein genes, cry6aa can be genetically recombined in Bt corn and Bt cotton so the plants produce specific toxins. Insects are developing resistance to the most commonly inserted proteins like Cry1Ac. Since Cry6Aa proteins function differently than other Cry proteins, they are combined with other proteins to decrease the development of pest resistance. Recent studies suggest this protein functions better in combination with other virulence factors such as other Cry proteins and metalloproteinases.>

References

  1. 1 2 3 4 5 6 7 8 Dietrich, Richard; Jessberger, Nadja; Ehling-Schulz, Monika; Märtlbauer, Erwin; Granum, Per Einar (February 2021). "The Food Poisoning Toxins of Bacillus cereus". Toxins. 13 (2): 98. doi: 10.3390/toxins13020098 . ISSN   2072-6651. PMC   7911051 . PMID   33525722.
  2. 1 2 Koné, Klèma Marcel; Hinnekens, Pauline; Jovanovic, Jelena; Rajkovic, Andreja; Mahillon, Jacques (2021-10-01). "New Insights into the Potential Cytotoxic Role of Bacillus cytotoxicus Cytotoxin K-1". Toxins. 13 (10): 698. doi: 10.3390/toxins13100698 . ISSN   2072-6651. PMC   8540763 . PMID   34678991.
  3. ↑ Tallent, S.M.; Hait, J.M.; Bennett, R.W. (April 2015). "Analysis of Bacillus cereus toxicity using PCR, ELISA and a lateral flow device". Journal of Applied Microbiology. 118 (4): 1068–1075. doi: 10.1111/jam.12766 . PMID   25627167. S2CID   25638015.
  4. ↑ Fagerlund, Annette; Ween, Ola; Lund, Terje; Hardy, Simon P.; Granum, Per E.YR 2004 (2004). "Genetic and functional analysis of the cytK family of genes in Bacillus cereus". Microbiology. 150 (8): 2689–2697. doi: 10.1099/mic.0.26975-0 . ISSN   1465-2080. PMID   15289565.
  5. 1 2 3 4 Lund, Terje; De Buyser, Marie-Laure; Granum, Per Einar (October 2000). "A new cytotoxin from Bacillus cereus that may cause necrotic enteritis". Molecular Microbiology. 38 (2): 254–261. doi: 10.1046/j.1365-2958.2000.02147.x . ISSN   0950-382X. PMID   11069652. S2CID   5729364.
  6. ↑ Song, Langzhou; Hobaugh, Michael R.; Shustak, Christopher; Cheley, Stephen; Bayley, Hagan; Gouaux, J. Eric (1996-12-13). "Structure of Staphylococcal α-Hemolysin, a Heptameric Transmembrane Pore". Science. 274 (5294): 1859–1865. Bibcode:1996Sci...274.1859S. doi:10.1126/science.274.5294.1859. ISSN   0036-8075. PMID   8943190. S2CID   45663016.
  7. 1 2 Desvaux, Mickaël; Hébraud, Michel (September 2006). "The protein secretion systems in Listeria : inside out bacterial virulence". FEMS Microbiology Reviews. 30 (5): 774–805. doi: 10.1111/j.1574-6976.2006.00035.x . ISSN   1574-6976. PMID   16911044.
  8. 1 2 3 4 5 Zhao, Yan; Sun, Li (4 July 2022). "Bacillus cereus cytotoxin K triggers gasdermin D-dependent pyroptosis". Cell Death Discovery. 8 (1): 305. doi:10.1038/s41420-022-01091-5. PMC   9253000 . PMID   35788609. S2CID   256605262.
  9. ↑ Shao, Bo-Zong; Xu, Zhe-Qi; Han, Bin-Ze; Su, Ding-Feng; Liu, Chong (2015). "NLRP3 inflammasome and its inhibitors: a review". Frontiers in Pharmacology. 6: 262. doi: 10.3389/fphar.2015.00262 . ISSN   1663-9812. PMC   4633676 . PMID   26594174.
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