Biology:Shiga toxin

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Short description: Family of related toxins
Ribbon diagram of Shiga toxin (Stx) from S. dysenteriae. From PDB: 1R4Q​.
Shiga-like toxin beta subunit
Identifiers
SymbolSLT_beta
PfamPF02258
InterProIPR003189
SCOP22bos / SCOPe / SUPFAM
TCDB1.C.54
Shiga-like toxin subunit A
Identifiers
SymbolShiga-like_toxin_subunit_A
InterProIPR016331
SCOP21r4q / SCOPe / SUPFAM

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.[1] The toxins are named after Kiyoshi Shiga, who first described the bacterial origin of dysentery caused by Shigella dysenteriae.[2] Shiga-like toxin (SLT) is a historical term for similar or identical toxins produced by Escherichia coli.[3] 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.[4][5]

Nomenclature

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.[6] Stx-2 shares 56% sequence identity with Stx-1.[citation needed]
  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.[7][8][9]
  4. The term Shiga-like toxins is another antiquated term which arose prior to the understanding that Shiga and Shiga-like toxins were identical.[10]

History

The toxin is named after Kiyoshi Shiga, who discovered S. dysenteriae in 1897.[2] In 1977, researchers in Ottawa, Ontario discovered the Shiga toxin normally produced by Shigella dysenteriae in a line of E. coli.[11] 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.[12] 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".[13]:2–3

Transmission

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.[14]

Clinical significance

Symptoms of Shiga toxin ingestion include abdominal pain as well as watery diarrhea. Severe life-threatening cases are characterized by hemorrhagic colitis (HC).[15]

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.

Structure and mechanism

SLT2 from Escherichia coli O157:H7. A-subunit is shown above (viridian), with B-subunit pentamer below (multicolored). From PDB: 1R4P​.

Mechanism

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 the bacterial uptake into the cell. These tubules are essential for uptake into the host cell.[16] 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. Shiga toxins act to inhibit protein synthesis within target cells by a mechanism similar to that of the infamous plant toxin ricin.[17][18] After entering a cell via a macropinosome,[19] the payload (A subunit) cleaves a specific adenine nucleobase from the 28S RNA of the 60S subunit of the ribosome, thereby halting protein synthesis.[20] As they mainly act on the lining of the blood 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 contaminated food or water.

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.[21]

Structure

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).[22][23] 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.[24] Stx-2 is also known to increase the expression of its receptor GB3 and cause neuronal dysfunctions.[25]

See also

References

  1. ↑ 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. PMID 11282477. 
  2. ↑ 2.0 2.1 Trofa, Andrew F.; Ueno-Olsen, Hannah; Oiwa, Ruiko; Yoshikawa, Masanosuke (1999-11-01). "Dr. Kiyoshi Shiga: Discoverer of the Dysentery Bacillus" (in en). Clinical Infectious Diseases 29 (5): 1303–1306. doi:10.1086/313437. ISSN 1058-4838. PMID 10524979. 
  3. ↑ Zhu Q; Li L; Guo Z; Yang R (June 2002). "Identification of Shiga-like toxin Escherichia coli isolated from children with diarrhea by polymerase chain reaction". Chin. Med. J. 115 (6): 815–8. PMID 12123543. http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2002&vol=115&issue=6&beginpage=815. 
  4. ↑ Beutin L (2006). "Emerging enterohaemorrhagic Escherichia coli, causes and effects of the rise of a human pathogen". Journal of Veterinary Medicine. B, Infectious Diseases and Veterinary Public Health 53 (7): 299–305. doi:10.1111/j.1439-0450.2006.00968.x. PMID 16930272. 
  5. ↑ Spears (2006). "A comparison of Enteropathogenic and enterohaemorragic E.coli pathogenesis". FEMS Microbiology Letters 255 (2): 187–202. doi:10.1111/j.1574-6968.2006.00119.x. PMID 16448495. 
  6. ↑ "Overview and Historical Perspectives". Microbiology Spectrum 2 (6). 2014. doi:10.1128/microbiolspec.EHEC-0028-2014. PMID 25590020. 
  7. ↑ Beutin L; Geier D; Steinrück H; Zimmermann S; Scheutz F (September 1993). "Prevalence and some properties of verotoxin (Shiga-like toxin)-producing Escherichia coli in seven different species of healthy domestic animals". Journal of Clinical Microbiology 31 (9): 2483–8. doi:10.1128/JCM.31.9.2483-2488.1993. PMID 8408571. 
  8. ↑ Bitzan M; Richardson S; Huang C; Boyd B; Petric M; Karmali MA (August 1994). "Evidence that verotoxins (Shiga-like toxins) from Escherichia coli bind to P blood group antigens of human erythrocytes in vitro". Infection and Immunity 62 (8): 3337–47. doi:10.1128/IAI.62.8.3337-3347.1994. PMID 8039905. 
  9. ↑ Giraldi R; Guth BE; Trabulsi LR (June 1990). "Production of Shiga-like toxin among Escherichia coli strains and other bacteria isolated from diarrhea in São Paulo, Brazil". Journal of Clinical Microbiology 28 (6): 1460–2. doi:10.1128/JCM.28.6.1460-1462.1990. PMID 2199511. 
  10. ↑ "Multicenter evaluation of a sequence-based protocol for subtyping Shiga toxins and standardizing Stx nomenclature". Journal of Clinical Microbiology 50 (9): 2951–63. September 2012. doi:10.1128/JCM.00860-12. PMID 22760050. 
  11. ↑ "Vero response to a cytotoxin of Escherichia coli". Infection and Immunity 18 (3): 775–9. December 1977. doi:10.1128/IAI.18.3.775-779.1977. PMID 338490. 
  12. ↑ "The so-called chromosomal verotoxin genes are actually carried by defective prophages". DNA Research 6 (2): 141–3. April 1999. doi:10.1093/dnares/6.2.141. PMID 10382973. 
  13. ↑ Silva, Christopher J. et al. (2017), "Chapter 3: Structure of Shiga toxins and other AB5 toxins", Shiga toxins: A Review of Structure, Mechanism, and Detection, Springer, ISBN 978-3319505800, https://books.google.com/books?id=nKQ7DgAAQBAJ&q=%22verocytotoxin+VCT%22&pg=PA22. 
  14. ↑ "Phylogenetic diversity and similarity of active sites of Shiga toxin (stx) in Shiga toxin-producing Escherichia coli (STEC) isolates from humans and animals". Epidemiology and Infection 127 (1): 27–36. August 2001. doi:10.1017/S0950268801005635. PMID 11561972. 
  15. ↑ Beutin, L; Miko, A; Krause, G; Pries, K; Haby, S; Steege, K; Albrecht, N (2007). "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". Applied and Environmental Microbiology 73 (15): 4769–75. doi:10.1128/AEM.00873-07. PMID 17557838. 
  16. ↑ "Shiga toxin induces tubular membrane invaginations for its uptake into cells". Nature 450 (7170): 670–5. November 2007. doi:10.1038/nature05996. PMID 18046403. Bibcode: 2007Natur.450..670R. https://resolver.sub.uni-goettingen.de/purl?gro-2/918. 
  17. ↑ "Entry of ricin and Shiga toxin into cells: molecular mechanisms and medical perspectives". The EMBO Journal 19 (22): 5943–50. November 2000. doi:10.1093/emboj/19.22.5943. PMID 11080141. 
  18. ↑ "Transcriptional network inference and master regulator analysis of the response to ribosome-inactivating proteins in leukemia cells". Toxicology 441: 152531. August 2020. doi:10.1016/j.tox.2020.152531. PMID 32593706. 
  19. ↑ "Enterohemorrhagic Escherichia coli infection stimulates Shiga toxin 1 macropinocytosis and transcytosis across intestinal epithelial cells". American Journal of Physiology. Cell Physiology 301 (5): C1140-9. November 2011. doi:10.1152/ajpcell.00036.2011. PMID 21832249. 
  20. ↑ "Shiga toxin: purification, structure, and function". Reviews of Infectious Diseases 13 Suppl 4 (7): S293-7. 2010. doi:10.1016/j.toxicon.2009.11.021. PMID 2047652. 
  21. ↑ Gastric adenocarcinomas express the glycosphingolipid Gb3/CD77: Targeting of gastric cancer cells with Shiga toxin B-subunit
  22. ↑ "Crystal structure of the cell-binding B oligomer of verotoxin-1 from E. coli". Nature 355 (6362): 748–50. February 1992. doi:10.1038/355748a0. PMID 1741063. Bibcode: 1992Natur.355..748S. 
  23. ↑ "Pathogenic Escherichia coli". Nature Reviews. Microbiology 2 (2): 123–40. February 2004. doi:10.1038/nrmicro818. PMID 15040260. 
  24. ↑ "Shiga toxin 2 affects the central nervous system through receptor globotriaosylceramide localized to neurons". The Journal of Infectious Diseases 198 (9): 1398–406. November 2008. doi:10.1086/591911. PMID 18754742. 
  25. ↑ "Intracerebroventricular Shiga toxin 2 increases the expression of its receptor globotriaosylceramide and causes dendritic abnormalities". Journal of Neuroimmunology 222 (1–2): 48–61. May 2010. doi:10.1016/j.jneuroim.2010.03.001. PMID 20347160. 

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