shiga toxin

Microbiologists use many terms to describe Shiga toxin and differentiate more than one unique form. Many of these terms are used interchangeably.

1. 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 of Shigella spp. or differs by only one amino acid.{{cite journal|vauthors=Kaper JB, O'Brien AD |title=Overview and Historical Perspectives |journal=Microbiology Spectrum |volume=2 |issue=6 |veditors=Sperandio V, Hovde CJ|year=2014 |pmid=25590020 |pmc=4290666 |doi=10.1128/microbiolspec.EHEC-0028-2014}} Stx-2 shares 55% amino acid homology with Stx-1.{{cite journal |last1=Kaper |first1=James B. |last2=Nataro |first2=James P. |last3=Mobley |first3=Harry L. T. |title=Pathogenic Escherichia coli |journal=Nature Reviews Microbiology |date=February 2004 |volume=2 |issue=2 |pages=123–140 |doi=10.1038/nrmicro818 |pmid=15040260 }}
2. Cytotoxins – an archaic denotation for Stx – is used in a broad sense.
3. Verocytotoxins/verotoxins – a seldom-used term for Stx – is from the hypersensitivity of Vero cells to Stx.{{cite journal |author1=Beutin L |author2=Geier D |author3=Steinrück H |author4=Zimmermann S |author5=Scheutz F |title=Prevalence and some properties of verotoxin (Shiga-like toxin)-producing Escherichia coli in seven different species of healthy domestic animals |journal=Journal of Clinical Microbiology |volume=31 |issue=9 |pages=2483–8 |date=September 1993 |pmid=8408571 |pmc=265781 |doi= 10.1128/JCM.31.9.2483-2488.1993}}{{cite journal |author1=Bitzan M |author2=Richardson S |author3=Huang C |author4=Boyd B |author5=Petric M |author6=Karmali MA |title=Evidence that verotoxins (Shiga-like toxins) from Escherichia coli bind to P blood group antigens of human erythrocytes in vitro |journal=Infection and Immunity |volume=62 |issue=8 |pages=3337–47 |date=August 1994 |pmid=8039905 |pmc=302964 |doi= 10.1128/IAI.62.8.3337-3347.1994}}{{cite journal |author1=Giraldi R |author2=Guth BE |author3=Trabulsi LR |title=Production of Shiga-like toxin among Escherichia coli strains and other bacteria isolated from diarrhea in São Paulo, Brazil |journal=Journal of Clinical Microbiology |volume=28 |issue=6 |pages=1460–2 |date=June 1990 |pmid=2199511 |pmc=267957 |doi= 10.1128/JCM.28.6.1460-1462.1990}}
4. The term Shiga-like toxins is another antiquated term which arose prior to the understanding that Shiga and Shiga-like toxins were identical.{{cite journal | vauthors = Scheutz F, Teel LD, Beutin L, Piérard D, Buvens G, Karch H, Mellmann A, Caprioli A, Tozzoli R, Morabito S, Strockbine NA, Melton-Celsa AR, Sanchez M, Persson S, O'Brien AD | title = Multicenter evaluation of a sequence-based protocol for subtyping Shiga toxins and standardizing Stx nomenclature | journal = Journal of Clinical Microbiology | volume = 50 | issue = 9 | pages = 2951–63 | date = September 2012 | pmid = 22760050 | pmc = 3421821 | doi = 10.1128/JCM.00860-12 }}

The toxin is named after Kiyoshi Shiga, who discovered S. dysenteriae in 1897. In 1977, researchers in Ottawa, Ontario discovered the Shiga toxin normally produced by Shigella dysenteriae in a line of E. coli.{{cite journal | vauthors = Konowalchuk J, Speirs JI, Stavric S | title = Vero response to a cytotoxin of Escherichia coli | journal = Infection and Immunity | volume = 18 | issue = 3 | pages = 775–9 | date = December 1977 | doi = 10.1128/IAI.18.3.775-779.1977 | pmid = 338490 | pmc = 421302 }} The E. coli version of the toxin was named "verotoxin" because of its ability to kill Vero cells (African green monkey kidney 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 lambdoid bacteriophage, such as H-19B or 933W, inserted into the bacteria's chromosome via transduction.{{cite journal | vauthors = Mizutani S, Nakazono N, Sugino Y | title = The so-called chromosomal verotoxin genes are actually carried by defective prophages | journal = DNA Research | volume = 6 | issue = 2 | pages = 141–3 | date = April 1999 | pmid = 10382973 | doi = 10.1093/dnares/6.2.141 | doi-access = free }} Phylogenetic studies of the diversity of E. coli suggest that it may have been relatively easy for Shiga toxin to transduce into certain strains of E. coli, because Shigella is itself a subgenus of Escherichia; in fact, some strains traditionally considered E. coli (including those that produce this toxin) in fact belong to this lineage. Being closer relatives of Shigella dysenteriae than of the typical E. coli, it is not at all unusual that toxins similar to that of S. 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".{{Citation |last1=Silva |first1=Christopher J. |last2=Brandon |first2=David L. |last3=Skinner |first3=Craig B. |last4=He |first4=Xiaohua |display-authors=etal | name-list-style = vanc |year=2017 |title=Shiga toxins: A Review of Structure, Mechanism, and Detection |chapter=Chapter 3: Structure of Shiga toxins and other AB5 toxins |publisher=Springer|chapter-url=https://books.google.com/books?id=nKQ7DgAAQBAJ&q=%22verocytotoxin+VCT%22&pg=PA22 |isbn=978-3319505800 |postscript=.}}{{rp|2–3}}

The toxin requires highly specific receptors on the cells' surface in order to attach and enter the cell; species such as cattle, swine, and deer which do not carry these receptors may harbor toxigenic bacteria without any ill effect, shedding them in their feces, from where they may be spread to humans.{{cite journal |last1=Asakura |first1=H. |last2=Makino |first2=S-I. |last3=Kobori |first3=H. |last4=Watarai |first4=M. |last5=Shirahata |first5=T. |last6=Ikeda |first6=T. |last7=Takeshi |first7=K. |title=Phylogenetic diversity and similarity of active sites of Shiga toxin (Stx) in Shiga toxin-producing Escherichia coli (STEC) isolates from humans and animals |journal=Epidemiology and Infection |date=April 2001 |volume=127 |issue=1 |pages=27–36 |doi=10.1017/s0950268801005635 |doi-broken-date=1 November 2024 |pmid=11561972 |pmc=2869726 }}

Symptoms of Shiga toxin ingestion include abdominal pain as well as watery diarrhea. Severe life-threatening cases are characterized by hemorrhagic colitis (HC).{{cite journal |last1=Beutin |first1=Lothar |last2=Miko |first2=Angelika |last3=Krause |first3=Gladys |last4=Pries |first4=Karin |last5=Haby |first5=Sabine |last6=Steege |first6=Katja |last7=Albrecht |first7=Nadine |title=Identification of Human-Pathogenic Strains of Shiga Toxin-Producing Escherichia coli from Food by a Combination of Serotyping and Molecular Typing of Shiga Toxin Genes |journal=Applied and Environmental Microbiology |date=August 2007 |volume=73 |issue=15 |pages=4769–4775 |doi=10.1128/AEM.00873-07 |pmid=17557838 |pmc=1951031 |bibcode=2007ApEnM..73.4769B }}

The toxin is associated with hemolytic-uremic syndrome. In contrast, Shigella species may also produce shigella enterotoxins, which are the cause of dysentery.

The toxin is effective against small blood vessels, such as found in the digestive tract, the kidney, and lungs, but not against large vessels such as the arteries or major veins. A specific target for the toxin appears to be the vascular endothelium of the glomerulus. 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 the nervous system.

File:1R4P Structure.png. A-subunit is shown above (viridian), with B-subunit pentamer below (multicolored). From {{PDB|1R4P}}.]]

The B subunits of the toxin bind to a component of the cell membrane known as glycolipid globotriaosylceramide (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{{cite journal|vauthors=Obrig TG|title=Escherichia coli Shiga Toxin Mechanisms of Action in Renal Disease|journal=Toxins|volume=2|issue=12|pages=2769–2794|doi=10.3390/toxins2122769|doi-access=free|year=2010|pmid=21297888|pmc=3032420}} uptake into the cell. These tubules are essential for uptake into the host cell.{{cite journal | vauthors = Römer W, Berland L, Chambon V, Gaus K, Windschiegl B, Tenza D, Aly MR, Fraisier V, Florent JC, Perrais D, Lamaze C, Raposo G, Steinem C, Sens P, Bassereau P, Johannes L | title = Shiga toxin induces tubular membrane invaginations for its uptake into cells | journal = Nature | volume = 450 | issue = 7170 | pages = 670–5 | date = November 2007 | pmid = 18046403 | doi = 10.1038/nature05996 | bibcode = 2007Natur.450..670R | s2cid = 4410673}}

The Shiga toxin (a non-pore forming toxin) is transferred to the cytosol via Golgi network and endoplasmic reticulum (ER). From the Golgi toxin is trafficked to the ER. It is then processed through cleavage by a furin-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.

Shiga toxins act to inhibit protein synthesis within target cells by a mechanism similar to that of the infamous plant toxin ricin.{{cite journal | vauthors = Sandvig K, van Deurs B | title = Entry of ricin and Shiga toxin into cells: molecular mechanisms and medical perspectives | journal = The EMBO Journal | volume = 19 | issue = 22 | pages = 5943–50 | date = November 2000 | pmid = 11080141 | pmc = 305844 | doi = 10.1093/emboj/19.22.5943 }}{{cite journal | vauthors = Mercatelli D, Bortolotti M, Giorgi FM | title = Transcriptional network inference and master regulator analysis of the response to ribosome-inactivating proteins in leukemia cells | journal = Toxicology | volume = 441 | date = August 2020 | page = 152531 | doi = 10.1016/j.tox.2020.152531 | pmid = 32593706 | bibcode = 2020Toxgy.44152531M | s2cid = 220255474 }} After entering a cell via a macropinosome,{{cite journal | vauthors = Lukyanenko V, Malyukova I, Hubbard A, Delannoy M, Boedeker E, Zhu C, Cebotaru L, Kovbasnjuk O | title = Enterohemorrhagic Escherichia coli infection stimulates Shiga toxin 1 macropinocytosis and transcytosis across intestinal epithelial cells | journal = American Journal of Physiology. Cell Physiology | volume = 301 | issue = 5 | pages = C1140-9 | date = November 2011 | pmid = 21832249 | pmc = 3213915 | doi = 10.1152/ajpcell.00036.2011 }} the payload (A subunit) cleaves a specific adenine nucleobase from the 28S RNA of the 60S subunit of the ribosome, thereby halting protein synthesis.{{cite journal | vauthors = Donohue-Rolfe A, Acheson DW, Keusch GT | title = Shiga toxin: purification, structure, and function | journal = Reviews of Infectious Diseases | volume = 13 Suppl 4 | issue = 7 | pages = S293-7 | year = 2010 | pmid = 2047652 | doi = 10.1016/j.toxicon.2009.11.021 }} As they mainly act on the lining of the blood vessels, the vascular endothelium, a breakdown of the lining and hemorrhage eventually occurs.{{clarify|date=December 2015}} {{citation needed span|text=The first response is commonly a bloody diarrhea. This is because Shiga toxin is usually taken in with contaminated food or water.|date=October 2024}}

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.Gastric adenocarcinomas express the glycosphingolipid Gb3/CD77: Targeting of gastric cancer cells with Shiga toxin B-subunit

The toxin has two subunits—designated A (mol. wt. 32000 Da) and B (mol. wt. 7700 Da)—and is one of the AB₅ toxins. The B subunit is a pentamer that binds to specific glycolipids on the host cell, specifically globotriaosylceramide (Gb3).{{cite journal | vauthors = Stein PE, Boodhoo A, Tyrrell GJ, Brunton JL, Read RJ | title = Crystal structure of the cell-binding B oligomer of verotoxin-1 from E. coli | journal = Nature | volume = 355 | issue = 6362 | pages = 748–50 | date = February 1992 | pmid = 1741063 | doi = 10.1038/355748a0 | bibcode = 1992Natur.355..748S | s2cid = 4274763 }}{{cite journal | vauthors = Kaper JB, Nataro JP, Mobley HL | title = Pathogenic Escherichia coli | journal = Nature Reviews. Microbiology | volume = 2 | issue = 2 | pages = 123–40 | date = February 2004 | pmid = 15040260 | doi = 10.1038/nrmicro818 | s2cid = 3343088 }} 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 to neurotoxicity.{{cite journal | vauthors = Obata F, Tohyama K, Bonev AD, Kolling GL, Keepers TR, Gross LK, Nelson MT, Sato S, Obrig TG | title = Shiga toxin 2 affects the central nervous system through receptor globotriaosylceramide localized to neurons | journal = The Journal of Infectious Diseases | volume = 198 | issue = 9 | pages = 1398–406 | date = November 2008 | pmid = 18754742 | pmc = 2684825 | doi = 10.1086/591911 }}

Stx-2 is also known to increase the expression of its receptor GB3 and cause neuronal dysfunctions.{{cite journal | vauthors = Tironi-Farinati C, Loidl CF, Boccoli J, Parma Y, Fernandez-Miyakawa ME, Goldstein J | title = Intracerebroventricular Shiga toxin 2 increases the expression of its receptor globotriaosylceramide and causes dendritic abnormalities | journal = Journal of Neuroimmunology | volume = 222 | issue = 1–2 | pages = 48–61 | date = May 2010 | pmid = 20347160 | doi = 10.1016/j.jneuroim.2010.03.001 | s2cid = 11910897 | hdl = 11336/16303 | hdl-access = free }}

• 2011 German E. coli outbreak
• Cholera toxin
• Enterotoxin
• Pertussis toxin

{{Reflist|30em}}

• UniprotKB entries: stxA1 {{uniprot|Q9FBI2}}, stxB1 {{uniprot|Q7BQ98}}, stxA2 {{uniprot|P09385}}, stxB2 {{uniprot|P09386}}
• {{MeshName|Shiga+toxin}}
• {{MeshName|Shiga-Like+Toxin+I}}
• {{MeshName|Shiga-Like+Toxin+II}}
• [http://www.textbookofbacteriology.net/Shigella.html "Shigella"] in Todar's Online Textbook of Bacteriology
• {{cite journal |last1=Mizutani |first1=S. |title=The So-called Chromosomal Verotoxin Genes are Actually Carried by Defective Prophages |journal=DNA Research |date=1999 |volume=6 |issue=2 |pages=141–143 |doi=10.1093/dnares/6.2.141 |pmid=10382973 |doi-access=free }}

{{Toxins}}

Category:AB5 toxins

Category:Bacterial toxins

Category:Biological toxin weapons

Category:Ribosome-inactivating proteins

Category:Invertebrate toxins

Category:Microbiology