Shiga toxins are a family of relatedtoxins with two major groups, Stx1 and Stx2, expressed by genes considered to be part of thegenome oflambdoidprophages.[1] The toxins are named afterKiyoshi Shiga, who first described the bacterial origin ofdysentery caused byShigella dysenteriae.[2]Shiga-like toxin (SLT) is a historical term for similar or identical toxins produced byEscherichia coli.[3] The most common sources for Shiga toxin are the bacteriaS. dysenteriae andsome serotypes ofEscherichia coli (shigatoxigenic or STEC), which includeserotypesO157:H7, andO104:H4.[4][5]
Shiga toxin type 1 and type 2 (Stx-1 and 2) are the Shiga toxins produced by some E. coli strains. Stx-1 is identical to Stx ofShigella spp. or differs by only one amino acid.[6] Stx-2 shares 55% amino acid homology with Stx-1.[7]
Cytotoxins – an archaic denotation for Stx – is used in a broadsense.
Verocytotoxins/verotoxins – a seldom-used term for Stx – is from the hypersensitivity ofVero cells to Stx.[8][9][10]
The term Shiga-like toxins is another antiquated term which arose prior to the understanding that Shiga and Shiga-like toxins were identical.[11]
The toxin is named afterKiyoshi Shiga, who discoveredS. dysenteriae in 1897.[2] In 1977, researchers inOttawa, Ontario discovered the Shiga toxin normally produced byShigella dysenteriae in a line ofE. coli.[12] TheE. coli version of the toxin was named "verotoxin" because of its ability to killVero cells (African green monkeykidney cells) in culture. Shortly after, the verotoxin was referred to as Shiga-like toxin because of its similarities to Shiga toxin.
It has been suggested by some researchers that the gene coding for Shiga-like toxin comes from a toxin-converting lambdoidbacteriophage, such as H-19B or 933W, inserted into thebacteria'schromosome viatransduction.[13]Phylogenetic studies of thediversity ofE. coli suggest that it may have been relatively easy for Shiga toxin to transduce into certain strains ofE. coli, becauseShigella is itself asubgenus ofEscherichia; in fact, some strains traditionally consideredE. coli (including those that produce this toxin) in fact belong to this lineage. Being closer relatives ofShigella dysenteriae than of thetypicalE. coli, it is not at all unusual that toxins similar to that ofS. dysenteriae are produced by these strains. As microbiology advances, the historical variation in nomenclature (which arose because of gradually advancing science in multiple places) is increasingly giving way to recognizing all of these molecules as "versions of the same toxin" rather than "different toxins".[14]: 2–3
The toxin requires highly specificreceptors on the cells' surface in order to attach and enter thecell;species such ascattle,swine, anddeer which do not carry these receptors may harbor toxigenic bacteria without any ill effect, shedding them in theirfeces, from where they may be spread to humans.[15]
Symptoms of Shiga toxin ingestion include abdominal pain as well as watery diarrhea. Severe life-threatening cases are characterized byhemorrhagic colitis (HC).[16]
The toxin is effective against small blood vessels, such as found in thedigestive tract, thekidney, andlungs, but not against large vessels such as thearteries or majorveins. A specific target for the toxin appears to be the vascular endothelium of theglomerulus. This is the filtering structure that is a key to the function of the kidney. Destroying these structures leads to kidney failure and the development of the often deadly and frequently debilitating hemolytic uremic syndrome.Food poisoning with Shiga toxin often also has effects on the lungs and thenervous system.
The B subunits of the toxin bind to a component of thecell membrane known as glycolipidglobotriaosylceramide (Gb3). Binding of the subunit B to Gb3 causes induction of narrow tubular membrane invaginations, which drives formation of inward membrane tubules for toxin-receptor complex[17] uptake into the cell. These tubules are essential for uptake into the host cell.[18]The Shiga toxin (a non-pore forming toxin) is transferred to the cytosol via Golgi network andendoplasmic reticulum (ER). From the Golgi toxin is trafficked to the ER. It is then processed through cleavage by afurin-like protease to separate the A1 subunit. Some toxin-receptor complexes reportedly bypass these steps and are transported to the nucleus rather than the cytosol, with unknown effects.[17]
Shiga toxins act to inhibitprotein synthesis within target cells by a mechanism similar to that of the infamous plant toxinricin.[19][20] After entering a cell via amacropinosome,[21] the payload (A subunit) cleaves a specific adeninenucleobase from the28S RNA of the60S subunit of the ribosome, thereby halting protein synthesis.[22] As they mainly act on the lining of theblood vessels, the vascular endothelium, a breakdown of the lining and hemorrhage eventually occurs.[clarification needed]The first response is commonly a bloody diarrhea. This is because Shiga toxin is usually taken in with contaminatedfood orwater.[citation needed]
The bacterial Shiga toxin can be used for targeted therapy of gastric cancer, because this tumor entity expresses the receptor of the Shiga toxin. For this purpose an unspecific chemotherapeutical is conjugated to the B-subunit to make it specific. In this way only the tumor cells, but not healthy cells, are destroyed during therapy.[23]
The toxin has two subunits—designated A (mol. wt. 32000 Da) and B (mol. wt. 7700 Da)—and is one of theAB5 toxins. The B subunit is apentamer that binds to specificglycolipids on the host cell, specificallyglobotriaosylceramide (Gb3).[24][25] Following this, the A subunit is internalised and cleaved into two parts. The A1 component then binds to the ribosome, disrupting protein synthesis. Stx-2 has been found to be about 400 times more toxic (as quantified by LD50 in mice) than Stx-1.
Gb3 is, for unknown reasons, present in greater amounts in renal epithelial tissues, to which the renal toxicity of Shiga toxin may be attributed. Gb3 is also found in central nervous system neurons and endothelium, which may lead toneurotoxicity.[26]Stx-2 is also known to increase the expression of its receptor GB3 and cause neuronal dysfunctions.[27]
^Friedman D; Court D (2001). "Bacteriophage lambda: alive and well and still doing its thing".Current Opinion in Microbiology.4 (2):201–7.doi:10.1016/S1369-5274(00)00189-2.PMID11282477.
^Beutin L (2006). "Emerging enterohaemorrhagic Escherichia coli, causes and effects of the rise of a human pathogen".Journal of Veterinary Medicine, Series B.53 (7):299–305.doi:10.1111/j.1439-0450.2006.00968.x.PMID16930272.
^Kaper, James B.; Nataro, James P.; Mobley, Harry L. T. (February 2004). "Pathogenic Escherichia coli".Nature Reviews Microbiology.2 (2):123–140.doi:10.1038/nrmicro818.PMID15040260.
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Mizutani, S. (1999). "The So-called Chromosomal Verotoxin Genes are Actually Carried by Defective Prophages".DNA Research.6 (2):141–143.doi:10.1093/dnares/6.2.141.PMID10382973.
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