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Shiga Toxin (Stx) Classification, Structure, and Function

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  • Author: Angela R. Melton-Celsa1
  • Editors: Vanessa Sperandio2, Carolyn J. Hovde3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; 2: University of Texas Southwestern Medical Center, Dallas, TX; 3: University of Idaho, Moscow, ID
  • Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013
  • Received 14 January 2014 Accepted 03 February 2014 Published 31 July 2014
  • Angela R. Melton-Celsa, angela.melton-celsa.ctr@usuhs.edu
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  • Abstract:

    Shiga toxin (Stx) is one of the most potent bacterial toxins known. Stx is found in 1 and in some serogroups of (called Stx1 in ). In addition to or instead of Stx1, some strains produce a second type of Stx, Stx2, that has the same mode of action as Stx/Stx1 but is antigenically distinct. Because subtypes of each toxin have been identified, the prototype toxin for each group is now designated Stx1a or Stx2a. The Stxs consist of two major subunits, an A subunit that joins noncovalently to a pentamer of five identical B subunits. The A subunit of the toxin injures the eukaryotic ribosome and halts protein synthesis in target cells. The function of the B pentamer is to bind to the cellular receptor, globotriaosylceramide, Gb3, found primarily on endothelial cells. The Stxs traffic in a retrograde manner within the cell, such that the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum. In humans infected with Stx-producing , the most serious manifestation of the disease, hemolytic-uremic syndrome, is more often associated with strains that produce Stx2a rather than Stx1a, and that relative toxicity is replicated in mice and baboons. Stx1a and Stx2a also exhibit differences in cytotoxicity to various cell types, bind dissimilarly to receptor analogs or mimics, induce differential chemokine responses, and have several distinctive structural characteristics.

  • Citation: Melton-Celsa A. 2014. Shiga Toxin (Stx) Classification, Structure, and Function. Microbiol Spectrum 2(4):EHEC-0024-2013. doi:10.1128/microbiolspec.EHEC-0024-2013.

Key Concept Ranking

Bacterial Proteins
0.52813655
Enzyme-Linked Immunosorbent Assay
0.45891142
Cholera Toxin
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References

1. Trofa AF, Ueno-Olsen H, Oiwa R, Yoshikawa M. 1999. Dr. Kiyoshi Shiga: discoverer of the dysentery bacillus. Clin Infect Dis 29:1303–1306. [PubMed][CrossRef]
2. Conradi H. 1903. Uber Iosliche, durch asptische Autolyse erhaltene Giftstoffe vonRuhr- und Typhus-Bazillen. Dtsch Med Wochenschr 29:26–28. [CrossRef]
3. Karmali MA, Steele BT, Petric M, Lim C. 1983. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli in stools. Lancet i:619–620. [PubMed][CrossRef]
4. O'Brien AO, Lively TA, Chen ME, Rothman SW, Formal SB. 1983. Escherichia coli O157:H7 strains associated with haemorrhagic colitis in the United States produce a Shigella dysenteriae 1 (SHIGA) like cytotoxin. Lancet i:702. [PubMed][CrossRef]
5. Calderwood SB, Mekalanos JJ. 1987. Iron regulation of Shiga-like toxin expression in Escherichia coli is mediated by the fur locus. J Bacteriol 169:4759–4764. [PubMed]
6. Dubos RJ, Geiger JW. 1946. Preparation and properties of Shiga toxin and toxoid. J Exp Med 84:143–156. [CrossRef]
7. O'Brien AD, LaVeck GD, Thompson MR, Formal SB. 1982. Production of Shigella dysenteriae type 1-like cytotoxin by Escherichia coli. J Infect Dis 146:763–769. [PubMed][CrossRef]
8. Luna-Gierke RE, Griffin PM, Gould LH, Herman K, Bopp CA, Strockbine N, Mody RK. 2014. Outbreaks of non-O157 Shiga toxin-producing Escherichia coli infection: USA. Epidemiol Infect 7:1–11. [PubMed][CrossRef]
9. Friedrich AW, Bielaszewska M, Zhang WL, Pulz M, Kuczius T, Ammon A, Karch H. 2002. Escherichia coli harboring Shiga toxin 2 gene variants: frequency and association with clinical symptoms. J Infect Dis 185:74–84. [PubMed][CrossRef]
10. Scheutz F, Teel LD, Beutin L, Pierard 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. 2012. Multicenter evaluation of a sequence-based protocol for subtyping Shiga toxins and standardizing Stx nomenclature. J Clin Microbiol 50:2951–2963. [PubMed][CrossRef]
11. Gupta SK, Strockbine N, Omondi M, Hise K, Fair MA, Mintz E. 2007. Emergence of Shiga toxin 1 genes within Shigella dysenteriae type 4 isolates from travelers returning from the Island of Hispanola. Am J Trop Med Hyg 76:1163–1165. [PubMed]
12. Beutin L, Strauch E, Fischer I. 1999. Isolation of Shigella sonnei lysogenic for a bacteriophage encoding gene for production of Shiga toxin. Lancet 353:1498. [PubMed][CrossRef]
13. Zhang W, Bielaszewska M, Kuczius T, Karch H. 2002. Identification, characterization, and distribution of a Shiga toxin 1 gene variant (stx(1c)) in Escherichia coli strains isolated from humans. J Clin Microbiol 40:1441–1446. [PubMed][CrossRef]
14. Ohmura-Hoshino M, Ho ST, Kurazono H, Igarashi K, Yamasaki S, Takeda Y. 2003. Genetic and immunological analysis of a novel variant of Shiga toxin 1 from bovine Escherichia coli strains and development of bead-ELISA to detect the variant toxin. Microbiol Immunol 47:717–725. [PubMed][CrossRef]
15. Friedrich AW, Borell J, Bielaszewska M, Fruth A, Tschape H, Karch H. 2003. Shiga toxin 1c-producing Escherichia coli strains: phenotypic and genetic characterization and association with human disease. J Clin Microbiol 41:2448–2453. [PubMed][CrossRef]
16. Kumar A, Taneja N, Kumar Y, Sharma M. 2012. Detection of Shiga toxin variants among Shiga toxin-forming Escherichia coli isolates from animal stool, meat and human stool samples in India. J Appl Microbiol 113:1208–1216. [PubMed][CrossRef]
17. Schmitt CK, McKee ML, O'Brien AD. 1991. Two copies of Shiga-like toxin II-related genes common in enterohemorrhagic Escherichia coli strains are responsible for the antigenic heterogeneity of the O157:H- strain E32511. Infect Immun 59:1065–1073. [PubMed]
18. Melton-Celsa AR, Darnell SC, O'Brien AD. 1996. Activation of Shiga-like toxins by mouse and human intestinal mucus correlates with virulence of enterohemorrhagic Escherichia coli O91:H21 isolates in orally infected, streptomycin-treated mice. Infect Immun 64:1569–1576. [PubMed]
19. Kokai-Kun JF, Melton-Celsa AR, O'Brien AD. 2000. Elastase in intestinal mucus enhances the cytotoxicity of Shiga toxin type 2d. J Biol Chem 275:3713–3721. [PubMed][CrossRef]
20. Bielaszewska M, Friedrich AW, Aldick T, Schurk-Bulgrin R, Karch H. 2006. Shiga toxin activatable by intestinal mucus in Escherichia coli isolated from humans: predictor for a severe clinical outcome. Clin Infect Dis 43:1160–1167. [PubMed][CrossRef]
21. Lindgren SW, Samuel JE, Schmitt CK, O'Brien AD. 1994. The specific activities of Shiga-like toxin type II (SLT-II) and SLT-II-related toxins of enterohemorrhagic Escherichia coli differ when measured by Vero cell cytotoxicity but not by mouse lethality. Infect Immun 62:623–631. [PubMed]
22. Lindgren SW, Melton AR, O'Brien AD. 1993. Virulence of enterohemorrhagic Escherichia coli O91:H21 clinical isolates in an orally infected mouse model. Infect Immun 61:3832–3842. [PubMed]
23. Fuller CA, Pellino CA, Flagler MJ, Strasser JE, Weiss AA. 2011. Shiga toxin subtypes display dramatic differences in potency. Infect Immun 79:1329–1337. [PubMed][CrossRef]
24. Pierard D, Muyldermans G, Moriau L, Stevens D, Lauwers S. 1998. Identification of new verocytotoxin type 2 variant B-subunit genes in human and animal Escherichia coli isolates. J Clin Microbiol 36:3317–3322. [PubMed]
25. Stephan R. Hoelzle LE. 2000. Characterization of Shiga toxin type 2 variant B-subunit in Escherichia coli strains from asymptomatic human carriers by PCR-RFLP. Lett Appl Microbiol 31:139–142. [PubMed][CrossRef]
26. Moxley RA. 2000. Edema disease. Vet Clin North Am Food Anim Pract 16:175–185. [PubMed]
27. Hovde CJ, Calderwood SB, Mekalanos JJ, Collier RJ. 1988. Evidence that glutamic acid 167 is an active-site residue of Shiga-like toxin I. Proc Natl Acad Sci USA 85:2568–2572. [PubMed][CrossRef]
28. Fraser ME, Fujinaga M, Cherney MM, Melton-Celsa AR, Twiddy EM, O'Brien AD, James MN. 2004. Structure of Shiga toxin type 2 (Stx2) from Escherichia coli O157:H7. J Biol Chem 279:27511–27517. [PubMed][CrossRef]
29. Melton-Celsa AR, Kokai-Kun JF, O'Brien AD. 2002. Activation of Shiga toxin type 2d (Stx2d) by elastase involves cleavage of the C-terminal two amino acids of the A2 peptide in the context of the appropriate B pentamer. Mol Microbiol 43:207–215. [PubMed][CrossRef]
30. Stein PE, Boodhoo A, Tyrrell GJ, Brunton JL, Read RJ. 1992. Crystal structure of the cell-binding B oligomer of verotoxin-1 from E. coli. Nature 355:748–750. [PubMed][CrossRef]
31. Fraser ME, Chernaia MM, Kozlov YV, James MN. 1994. Crystal structure of the holotoxin from Shigella dysenteriae at 2.5 A resolution. Nat Struct Biol 1:59–64. [PubMed][CrossRef]
32. Fraser ME, Cherney MM, Marcato P, Mulvey GL, Armstrong GD, James MN. 2006. Binding of adenine to Stx2, the protein toxin from Escherichia coli O157:H7. Acta Crystallogr Sect F Struct Biol Cryst Commun 62:627–630. [PubMed][CrossRef]
33. Richardson JM, Evans PD, Homans SW, Donohue-Rolfe A. 1997. Solution structure of the carbohydrate-binding B-subunit homopentamer of verotoxin VT-1 from E. coli. Nat Struct Biol 4:190–193. [PubMed][CrossRef]
34. Shimizu H, Field RA, Homans SW, Donohue-Rolfe A. 1998. Solution structure of the complex between the B-subunit homopentamer of verotoxin VT-1 from Escherichia coli and the trisaccharide moiety of globotriaosylceramide. Biochemistry 37:11078–11082. [PubMed][CrossRef]
35. Ling H, Boodhoo A, Hazes B, Cummings MD, Armstrong GD, Brunton JL, Read RJ. 1998. Structure of the Shiga-like toxin I B-pentamer complexed with an analogue of its receptor Gb3. Biochemistry 37:1777–1788. [PubMed][CrossRef]
36. Aletrari MO, McKibbin C, Williams H, Pawar V, Pietroni P, Lord JM, Flitsch SL, Whitehead R, Swanton E, High S, Spooner RA. 2011. Eeyarestatin 1 interferes with both retrograde and anterograde intracellular trafficking pathways. PLoS One 6:e22713. [PubMed][CrossRef]
37. Deresiewicz RL, Calderwood SB, Robertus JD, Collier RJ. 1992. Mutations affecting the activity of the Shiga-like toxin I A-chain. Biochemistry 31:3272–3280. [PubMed][CrossRef]
38. Di R, Kyu E, Shete V, Saidasan H, Kahn PC, Tumer NE. 2011. Identification of amino acids critical for the cytotoxicity of Shiga toxin 1 and 2 in Saccharomyces cerevisiae. Toxicon 57:525–539. [PubMed][CrossRef]
39. LaPointe P, Wei X, Gariepy J. 2005. A role for the protease-sensitive loop region of Shiga-like toxin 1 in the retrotranslocation of its A1 domain from the endoplasmic reticulum lumen. J Biol Chem 280:23310–23318. [PubMed][CrossRef]
40. McCluskey AJ, Poon GM, Bolewska-Pedyczak E, Srikumar T, Jeram SM, Raught B, Gariepy J. 2008. The catalytic subunit of Shiga-like toxin 1 interacts with ribosomal stalk proteins and is inhibited by their conserved C-terminal domain. J Mol Biol 378:375–386. [PubMed][CrossRef]
41. McCluskey AJ, Bolewska-Pedyczak E, Jarvik N, Chen G, Sidhu SS, Gariepy J. 2012. Charged and hydrophobic surfaces on the a chain of Shiga-like toxin 1 recognize the C-terminal domain of ribosomal stalk proteins. PLoS One 7:e31191. [PubMed][CrossRef]
42. Lindberg AA, Brown JE, Stromberg N, Westling-Ryd M, Schultz JE, Karlsson KA. 1987. Identification of the carbohydrate receptor for Shiga toxin produced by Shigella dysenteriae type 1. J Biol Chem 262:1779–1785. [PubMed]
43. Lingwood CA, Law H, Richardson S, Petric M, Brunton JL, De Grandis S, Karmali M. 1987. Glycolipid binding of purified and recombinant Escherichia coli produced verotoxin in vitro. J Biol Chem 262:8834–8839. [PubMed]
44. Waddell T, Head S, Petric M, Cohen A, Lingwood C. 1988. Globotriosyl ceramide is specifically recognized by the Escherichia coli verocytotoxin 2. Biochem Biophys Res Commun 152:674–679. [PubMed][CrossRef]
45. Jacewicz MS, Mobassaleh M, Gross SK, Balasubramanian KA, Daniel PF, Raghavan S, McCluer RH, Keusch GT. 1994. Pathogenesis of Shigella diarrhea: XVII. A mammalian cell membrane glycolipid, Gb3, is required but not sufficient to confer sensitivity to Shiga toxin. J Infect Dis 169:538–546. [PubMed][CrossRef]
46. Acheson DW, Moore R, De Breucker S, Lincicome L, Jacewicz M, Skutelsky E, Keusch GT. 1996. Translocation of Shiga toxin across polarized intestinal cells in tissue culture. Infect Immun 64:3294–3300. [PubMed]
47. Okuda T, Tokuda N, Numata S, Ito M, Ohta M, Kawamura K, Wiels J, Urano T, Tajima O, Furukawa K. 2006. Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins. J Biol Chem 281:10230–10235. [PubMed][CrossRef]
48. Tarabuso AL. 2011. Fabry disease. Skinmed 9:173–177. [PubMed]
49. Cilmi SA, Karalius BJ, Choy W, Smith RN, Butterton JR. 2006. Fabry disease in mice protects against lethal disease caused by Shiga toxin-expressing enterohemorrhagic Escherichia coli. J Infect Dis 194:1135–1140. [PubMed][CrossRef]
50. Nakajima H, Kiyokawa N, Katagiri YU, Taguchi T, Suzuki T, Sekino T, Mimori K, Ebata T, Saito M, Nakao H, Takeda T, Fujimoto J. 2001. Kinetic analysis of binding between Shiga toxin and receptor glycolipid Gb3Cer by surface plasmon resonance. J Biol Chem 276:42915–42922. [PubMed][CrossRef]
51. DeGrandis S, Law H, Brunton J, Gyles C, Lingwood CA. 1989. Globotetraosylceramide is recognized by the pig edema disease toxin. J Biol Chem 264:12520–12525. [PubMed]
52. Samuel JE, Perera LP, Ward S, O'Brien AD, Ginsburg V, Krivan HC. 1990. Comparison of the glycolipid receptor specificities of Shiga-like toxin type II and Shiga-like toxin type II variants. Infect Immun 58:611–618. [PubMed]
53. Devenish J, Gyles C, LaMarre J. 1998. Binding of Escherichia coli verotoxins to cell surface protein on wild-type and globotriaosylceramide-deficient Vero cells. Can J Microbiol 44:28–34. [PubMed][CrossRef]
54. Katagiri YU, Mori T, Nakajima H, Katagiri C, Taguchi T, Takeda T, Kiyokawa N, Fujimoto J. 1999. Activation of Src family kinase yes induced by Shiga toxin binding to globotriaosyl ceramide (Gb3/CD77) in low density, detergent-insoluble microdomains. J Biol Chem 274:35278–35282. [PubMed][CrossRef]
55. Kovbasnjuk O, Edidin M, Donowitz M. 2001. Role of lipid rafts in Shiga toxin 1 interaction with the apical surface of Caco-2 cells. J Cell Sci 114:4025–4031. [PubMed]
56. Falguieres T, Romer W, Amessou M, Afonso C, Wolf C, Tabet JC, Lamaze C, Johannes L. 2006. Functionally different pools of Shiga toxin receptor, globotriaosyl ceramide, in HeLa cells. FEBS J 273:5205–5218. [PubMed][CrossRef]
57. Kiarash A, Boyd B, Lingwood CA. 1994. Glycosphingolipid receptor function is modified by fatty acid content. Verotoxin 1 and verotoxin 2c preferentially recognize different globotriaosyl ceramide fatty acid homologues. J Biol Chem 269:11138–11146. [PubMed]
58. Pellizzari A, Pang H, Lingwood CA. 1992. Binding of verocytotoxin 1 to its receptor is influenced by differences in receptor fatty acid content. Biochemistry 31:1363–1370. [PubMed][CrossRef]
59. Khan F, Proulx F, Lingwood CA. 2009. Detergent-resistant globotriaosyl ceramide may define verotoxin/glomeruli-restricted hemolytic uremic syndrome pathology. Kidney Int 75:1209–1216. [PubMed][CrossRef]
60. Nyholm PG, Magnusson G, Zheng Z, Norel R, Binnington-Boyd B, Lingwood CA. 1996. Two distinct binding sites for globotriaosyl ceramide on verotoxins: identification by molecular modelling and confirmation using deoxy analogues and a new glycolipid receptor for all verotoxins. Chem Biol 3:263–275. [PubMed][CrossRef]
61. Thompson GS, Shimizu H, Homans SW, Donohue-Rolfe A. 2000. Localization of the binding site for the oligosaccharide moiety of Gb3 on verotoxin 1 using NMR residual dipolar coupling measurements. Biochemistry 39:13153–13156. [PubMed][CrossRef]
62. Bast DJ, Banerjee L, Clark C, Read RJ, Brunton JL. 1999. The identification of three biologically relevant globotriaosyl ceramide receptor binding sites on the Verotoxin 1 B subunit. Mol Microbiol 32:953–960. [PubMed][CrossRef]
63. Soltyk AM, MacKenzie CR, Wolski VM, Hirama T, Kitov PI, Bundle DR, Brunton JL. 2002. A mutational analysis of the globotriaosylceramide-binding sites of verotoxin VT1. J Biol Chem 277:5351–5359. [PubMed][CrossRef]
64. Kitova EN, Kitov PI, Paszkiewicz E, Kim J, Mulvey GL, Armstrong GD, Bundle DR, Klassen JS. 2007. Affinities of Shiga toxins 1 and 2 for univalent and oligovalent Pk-trisaccharide analogs measured by electrospray ionization mass spectrometry. Glycobiology 17:1127–1137. [PubMed][CrossRef]
65. Nishikawa K, Matsuoka K, Watanabe M, Igai K, Hino K, Hatano K, Yamada A, Abe N, Terunuma D, Kuzuhara H, Natori Y. 2005. Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation. J Infect Dis 191:2097–2105. [PubMed][CrossRef]
66. Watanabe M, Igai K, Matsuoka K, Miyagawa A, Watanabe T, Yanoshita R, Samejima Y, Terunuma D, Natori Y, Nishikawa K. 2006. Structural analysis of the interaction between Shiga toxin B subunits and linear polymers bearing clustered globotriose residues. Infect Immun 74:1984–1988. [PubMed][CrossRef]
67. Holgersson J, Jovall PA, Breimer ME. 1991. Glycosphingolipids of human large intestine: detailed structural characterization with special reference to blood group compounds and bacterial receptor structures. J Biochem 110:120–131. [PubMed]
68. Malyukova I, Murray KF, Zhu C, Boedeker E, Kane A, Patterson K, Peterson JR, Donowitz M, Kovbasnjuk O. 2009. Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis. Am J Physiol Gastrointest Liver Physiol 296:G78–92. [PubMed][CrossRef]
69. Hurley BP, Thorpe CM, Acheson DW. 2001. Shiga toxin translocation across intestinal epithelial cells is enhanced by neutrophil transmigration. Infect Immun 69:6148–6155. [PubMed][CrossRef]
70. Philpott DJ, Ackerley CA, Kiliaan AJ, Karmali MA, Perdue MH, Sherman PM. 1997. Translocation of verotoxin-1 across T84 monolayers: mechanism of bacterial toxin penetration of epithelium. Am J Physiol 273:G1349–1358. [PubMed]
71. Schuller S, Frankel G, Phillips AD. 2004. Interaction of Shiga toxin from Escherichia coli with human intestinal epithelial cell lines and explants: Stx2 induces epithelial damage in organ culture. Cell Microbiol 6:289–301. [PubMed][CrossRef]
72. Zumbrun SD, Hanson L, Sinclair JF, Freedy J, Melton-Celsa AR, Rodriguez-Canales J, Hanson JC, O'Brien AD. 2010. Human intestinal tissue and cultured colonic cells contain globotriaosylceramide synthase mRNA and the alternate Shiga toxin receptor globotetraosylceramide. Infect Immun 78:4488–4499. [PubMed][CrossRef]
73. Jacewicz MS, Acheson DW, Mobassaleh M, Donohue-Rolfe A, Balasubramanian KA, Keusch GT. 1995. Maturational regulation of globotriaosylceramide, the Shiga-like toxin 1 receptor, in cultured human gut epithelial cells. J Clin Invest 96:1328–1335. [PubMed][CrossRef]
74. Zumbrun SD, Melton-Celsa AR, Smith MA, Gilbreath JJ, Merrell DS, O'Brien AD. 2013. Dietary choice affects Shiga toxin-producing Escherichia coli (STEC) O157:H7 colonization and disease. Proc Natl Acad Sci USA 110:E2126–2133. [PubMed][CrossRef]
75. Schuller S, Heuschkel R, Torrente F, Kaper JB, Phillips AD. 2007. Shiga toxin binding in normal and inflamed human intestinal mucosa. Microbes Infect 9:35–39. [PubMed][CrossRef]
76. Bergan J, Dyve Lingelem AB, Simm R, Skotland T, Sandvig K. 2012. Shiga toxins. Toxicon 60:1085–1107. [PubMed][CrossRef]
77. Torgersen ML, Lauvrak SU, Sandvig K. 2005. The A-subunit of surface-bound Shiga toxin stimulates clathrin-dependent uptake of the toxin. FEBS J 272:4103–4113. [PubMed][CrossRef]
78. Romer 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. 2007. Shiga toxin induces tubular membrane invaginations for its uptake into cells. Nature 450:670–675. [PubMed][CrossRef]
79. Sandvig K, Garred O, Prydz K, Kozlov JV, Hansen SH, van Deurs B. 1992. Retrograde transport of endocytosed Shiga toxin to the endoplasmic reticulum. Nature 358:510–512. [PubMed][CrossRef]
80. Sandvig K, Bergan J, Dyve AB, Skotland T, Torgersen ML. 2010. Endocytosis and retrograde transport of Shiga toxin. Toxicon 56:1181–1185. [PubMed][CrossRef]
81. Garred O, van Deurs B, Sandvig K. 1995. Furin-induced cleavage and activation of Shiga toxin. J Biol Chem 270:10817–10821. [PubMed][CrossRef]
82. Raa H, Grimmer S, Schwudke D, Bergan J, Walchli S, Skotland T, Shevchenko A, Sandvig K. 2009. Glycosphingolipid requirements for endosome-to-Golgi transport of Shiga toxin. Traffic 10:868–882. [PubMed][CrossRef]
83. Sandvig K, Skotland T, van Deurs B, Klokk TI. 2013. Retrograde transport of protein toxins through the Golgi apparatus. Histochem Cell Biol 140:317–326. [PubMed][CrossRef]
84. Spooner RA, Lord JM. 2012. How ricin and Shiga toxin reach the cytosol of target cells: retrotranslocation from the endoplasmic reticulum. Curr Top Microbiol Immunol 357:19–40. [PubMed][CrossRef]
85. Tam PJ, Lingwood CA. 2007. Membrane cytosolic translocation of verotoxin A1 subunit in target cells. Microbiology 153:2700–2710. [PubMed][CrossRef]
86. Obrig TG, Moran TP, Brown JE. 1987. The mode of action of Shiga toxin on peptide elongation of eukaryotic protein synthesis. Biochem J 244:287–294. [PubMed]
87. Furutani M, Kashiwagi K, Ito K, Endo Y, Igarashi K. 1992. Comparison of the modes of action of a Vero toxin (a Shiga-like toxin) from Escherichia coli, of ricin, and of alpha-sarcin. Arch Biochem Biophys 293:140–146. [PubMed][CrossRef]
88. Warnier M, Romer W, Geelen J, Lesieur J, Amessou M, van den Heuvel L, Monnens L, Johannes L. 2006. Trafficking of Shiga toxin/Shiga-like toxin-1 in human glomerular microvascular endothelial cells and human mesangial cells. Kidney Int 70:2085–2091. [PubMed]
89. Jandhyala DM, Thorpe CM, Magun B. 2012. Ricin and Shiga toxins: effects on host cell signal transduction. Curr Top Microbiol Immunol 357:41–65. [PubMed][CrossRef]
90. Lee MS, Kim MH, Tesh VL. 2013. Shiga toxins expressed by human pathogenic bacteria induce immune responses in host cells. J Microbiol 51:724–730. [PubMed][CrossRef]
91. Tesh VL. 2012. The induction of apoptosis by Shiga toxins and ricin. Curr Top Microbiol Immunol 357:137–178. [PubMed][CrossRef]
92. Pai CH, Kelly JK, Meyers GL. 1986. Experimental infection of infant rabbits with verotoxin-producing Escherichia coli. Infect Immun 51:16–23. [PubMed]
93. Keenan KP, Sharpnack DD, Collins H, Formal SB, O'Brien AD. 1986. Morphologic evaluation of the effects of Shiga toxin and E. coli Shiga-like toxin on the rabbit intestine. Am J Pathol 125:69–80. [PubMed]
94. Tesh VL, Burris JA, Owens JW, Gordon VM, Wadolkowski EA, O'Brien AD, Samuel JE. 1993. Comparison of the relative toxicities of Shiga-like toxins type I and type II for mice. Infect Immun 61:3392–3402. [PubMed]
95. Smith MJ, Teel LD, Carvalho HM, Melton-Celsa AR, O'Brien AD. 2006. Development of a hybrid Shiga holotoxoid vaccine to elicit heterologous protection against Shiga toxins types 1 and 2. Vaccine 24:4122–4129. [PubMed][CrossRef]
96. Soborg B, Lassen SG, Muller L, Jensen T, Ethelberg S, Molbak K, Scheutz F. 2013. A verocytotoxin-producing E. coli outbreak with a surprisingly high risk of haemolytic uraemic syndrome, Denmark, September–October 2012. Euro Surveill 18:ii, 20350. [PubMed]
97. Boerlin P, McEwen SA, Boerlin-Petzold F, Wilson JB, Johnson RP, Gyles CL. 1999. Associations between virulence factors of Shiga toxin-producing Escherichia coli and disease in humans. J Clin Microbiol 37:497–503. [PubMed]
98. Ostroff SM, Tarr PI, Neill MA, Lewis JH, Hargrett-Bean N, Kobayashi JM. 1989. Toxin genotypes and plasmid profiles as determinants of systemic sequelae in Escherichia coli O157:H7 infections. J Infect Dis 160:994–998. [PubMed][CrossRef]
99. Russo LM, Melton-Celsa AR, Smith MA, Smith MJ, O'Brien DA. 2013. Oral intoxication of mice with Shiga toxin type 2a (Stx2a) and protection by anti-Stx2a monoclonal antibody 11E10. Infect Immun 82:1213–1221. [PubMed][CrossRef]
100. Louise CB, Obrig TG. 1995. Specific interaction of Escherichia coli O157:H7-derived Shiga-like toxin II with human renal endothelial cells. J Infect Dis 172:1397–1401. [PubMed][CrossRef]
101. Chark D, Nutikka A, Trusevych N, Kuzmina J, Lingwood C. 2004. Differential carbohydrate epitope recognition of globotriaosyl ceramide by verotoxins and a monoclonal antibody. Eur J Biochem 271:405–417. [PubMed][CrossRef]
102. Head SC, Karmali MA, Lingwood CA. 1991. Preparation of VT1 and VT2 hybrid toxins from their purified dissociated subunits. Evidence for B subunit modulation of a subunit function. J Biol Chem 266:3617–3621. [PubMed]
103. Gallegos KM, Conrady DG, Karve SS, Gunasekera TS, Herr AB, Weiss AA. 2012. Shiga toxin binding to glycolipids and glycans. PLoS One 7:e30368. [PubMed][CrossRef]
104. Mahfoud R, Manis A, Binnington B, Ackerley C, Lingwood CA. 2010. A major fraction of glycosphingolipids in model and cellular cholesterol-containing membranes is undetectable by their binding proteins. J Biol Chem 285:36049–36059. [PubMed][CrossRef]
105. Gamage SD, McGannon CM, Weiss AA. 2004. Escherichia coli serogroup O107/O117 lipopolysaccharide binds and neutralizes Shiga toxin 2. J Bacteriol 186:5506–5512. [PubMed][CrossRef]
106. Kimura T, Tani S, Matsumoto Yi Y, Takeda T. 2001. Serum amyloid P component is the Shiga toxin 2-neutralizing factor in human blood. J Biol Chem 276:41576–41579. [PubMed][CrossRef]
107. Conrady DG, Flagler MJ, Friedmann DR, Vander Wielen BD, Kovall RA, Weiss AA, Herr AB. 2010. Molecular basis of differential B-pentamer stability of Shiga toxins 1 and 2. PLoS One 5:e15153. [PubMed][CrossRef]
108. Tam P, Mahfoud R, Nutikka A, Khine AA, Binnington B, Paroutis P, Lingwood C. 2008. Differential intracellular transport and binding of verotoxin 1 and verotoxin 2 to globotriaosylceramide-containing lipid assemblies. J Cell Physiol 216:750–763. [PubMed][CrossRef]
109. Matussek A, Lauber J, Bergau A, Hansen W, Rohde M, Dittmar KE, Gunzer M, Mengel M, Gatzlaff P, Hartmann M, Buer J, Gunzer F. 2003. Molecular and functional analysis of Shiga toxin-induced response patterns in human vascular endothelial cells. Blood 102:1323–1332. [PubMed][CrossRef]
110. Lentz EK, Leyva-Illades D, Lee MS, Cherla RP, Tesh VL. 2011. Differential response of the human renal proximal tubular epithelial cell line HK-2 to Shiga toxin types 1 and 2. Infect Immun 79:3527–3540. [PubMed][CrossRef]
111. Stearns-Kurosawa DJ, Collins V, Freeman S, Tesh VL, Kurosawa S. 2010. Distinct physiologic and inflammatory responses elicited in baboons after challenge with Shiga toxin type 1 or 2 from enterohemorrhagic Escherichia coli. Infect Immun 78:2497–2504. [PubMed][CrossRef]
112. Bu F, Borsa N, Gianluigi A, Smith RJ. 2012. Familial atypical hemolytic uremic syndrome: a review of its genetic and clinical aspects. Clin Dev Immunol 2012:370426. [PubMed][CrossRef]
113. Riley LW, Remis RS, Helgerson SD, McGee HB, Wells JG, Davis BR, Hebert RJ, Olcott ES, Johnson LM, Hargrett NT, Blake PA, Cohen ML. 1983. Hemorrhagic colitis associated with a rare Escherichia coli serotype. N Engl J Med 308:681–685. [PubMed][CrossRef]
114. Frank C, Werber D, Cramer JP, Askar M, Faber M, an der Heiden M, Bernard H, Fruth A, Prager R, Spode A, Wadl M, Zoufaly A, Jordan S, Kemper MJ, Follin P, Muller L, King LA, Rosner B, Buchholz U, Stark K, Krause G. 2011. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 365:1771–1780. [PubMed][CrossRef]
115. Sauter KA, Melton-Celsa AR, Larkin K, Troxell ML, O'Brien AD, Magun BE. 2008. Mouse model of hemolytic-uremic syndrome caused by endotoxin-free Shiga toxin 2 (Stx2) and protection from lethal outcome by anti-Stx2 antibody. Infect Immun 76:4469–4478. [PubMed][CrossRef]
116. Fontaine A, Arondel J, Sansonetti PJ. 1988. Role of Shiga toxin in the pathogenesis of bacillary dysentery, studied by using a Tox- mutant of Shigella dysenteriae 1. Infect Immun 56:3099–3109. [PubMed]
117. Chaisri U, Nagata M, Kurazono H, Horie H, Tongtawe P, Hayashi H, Watanabe T, Tapchaisri P, Chongsa-nguan M, Chaicumpa W. 2001. Localization of Shiga toxins of enterohaemorrhagic Escherichia coli in kidneys of paediatric and geriatric patients with fatal haemolytic uraemic syndrome. Microb Pathog 31:59–67. [PubMed][CrossRef]
118. Uchida H, Kiyokawa N, Horie H, Fujimoto J, Takeda T. 1999. The detection of Shiga toxins in the kidney of a patient with hemolytic uremic syndrome. Pediatr Res 45:133–137. [PubMed][CrossRef]
119. Tazzari PL, Ricci F, Carnicelli D, Caprioli A, Tozzi AE, Rizzoni G, Conte R, Brigotti M. 2004. Flow cytometry detection of Shiga toxins in the blood from children with hemolytic uremic syndrome. Cytometry B Clin Cytom 61:40–44. [PubMed][CrossRef]
120. Bitzan M, Poole R, Mehran M, Sicard E, Brockus C, Thuning-Roberson C, Riviere M. 2009. Safety and pharmacokinetics of chimeric anti-Shiga toxin 1 and anti-Shiga toxin 2 monoclonal antibodies in healthy volunteers. Antimicrob Agents Chemother 53:3081–3087. [PubMed][CrossRef]
121. Dowling TC, Chavaillaz PA, Young DG, Melton-Celsa A, O'Brien A, Thuning-Roberson C, Edelman R, Tacket CO. 2005. Phase 1 safety and pharmacokinetic study of chimeric murine-human monoclonal antibody c alpha Stx2 administered intravenously to healthy adult volunteers. Antimicrob Agents Chemother 49:1808–1812. [PubMed][CrossRef]
122. McKee ML, Melton-Celsa AR, Moxley RA, Francis DH, O'Brien AD. 1995. Enterohemorrhagic Escherichia coli O157:H7 requires intimin to colonize the gnotobiotic pig intestine and to adhere to HEp-2 cells. Infect Immun 63:3739–3744. [PubMed]
123. Judge NA, Mason HS, O'Brien AD. 2004. Plant cell-based intimin vaccine given orally to mice primed with intimin reduces time of Escherichia coli O157:H7 shedding in feces. Infect Immun 72:168–175. [PubMed][CrossRef]
124. Girardeau JP, Dalmasso A, Bertin Y, Ducrot C, Bord S, Livrelli V, Vernozy-Rozand C, Martin C. 2005. Association of virulence genotype with phylogenetic background in comparison to different seropathotypes of Shiga toxin-producing Escherichia coli isolates. J Clin Microbiol 43:6098–6107. [PubMed][CrossRef]
125. Zumbrun SD, Melton-Celsa AR, O'Brien AD. 2014. When a healthy diet turns deadly. Gut Microbes 5(1):40–43. [PubMed][CrossRef]
126. Petruzziello-Pellegrini TN, Moslemi-Naeini M, Marsden PA. 2013. New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome. Virulence 4:556–563. [PubMed][CrossRef]
127. Keir LS, Saleem MA. 2013. Current evidence for the role of complement in the pathogenesis of Shiga toxin haemolytic uraemic syndrome. Pediatr Nephrol Jul 11. (Epub ahead of print.) [PubMed]
128. Zoja C, Buelli S, Morigi M. 2010. Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction. Pediatr Nephrol 25:2231–2240. [PubMed][CrossRef]
129. Andreoli SP, Trachtman H, Acheson DW, Siegler RL, Obrig TG. 2002. Hemolytic uremic syndrome: epidemiology, pathophysiology, and therapy. Pediatr Nephrol 17:293–298. [PubMed][CrossRef]
130. Maye CL, Leibowitz CS, Kurosawa S, Stearns-Kurosawa DJ. 2012. Shiga toxins and the pathophysiology of hemolytic uremic syndrome in humans and animals. Toxins (Basel) 4:1261–1287. [PubMed][CrossRef]
131. Stahl AL, Sartz L, Karpman D. 2011. Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Blood 117:5503–5513. [PubMed][CrossRef]
132. Thurman JM, Marians R, Emlen W, Wood S, Smith C, Akana H, Holers VM, Lesser M, Kline M, Hoffman C, Christen E, Trachtman H. 2009. Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 4:1920–1924. [PubMed][CrossRef]
133. Hale TL, Formal SB. 1980. Cytotoxicity of Shigella dysenteriae 1 for cultured mammalian cells. Am J Clin Nutr 33:2485–2490. [PubMed]
134. Koch C, Hertwig S, Lurz R, Appel B, Beutin L. 2001. Isolation of a lysogenic bacteriophage carrying the stx(1(OX3)) gene, which is closely associated with Shiga toxin-producing Escherichia coli strains from sheep and humans. J Clin Microbiol 39:3992–3998. [PubMed][CrossRef]
135. Paton AW, Beutin L, Paton JC. 1995. Heterogeneity of the amino-acid sequences of Escherichia coli Shiga-like toxin type-I operons. Gene 153:71–74. [PubMed][CrossRef]
136. Burk C, Dietrich R, Acar G, Moravek M, Bulte M, Martlbauer E. 2003. Identification and characterization of a new variant of Shiga toxin 1 in Escherichia coli ONT:H19 of bovine origin. J Clin Microbiol 41:2106–2112. [PubMed][CrossRef]
137. Paton AW, Paton JC, Manning PA. 1993. Polymerase chain reaction amplification, cloning and sequencing of variant Escherichia coli Shiga-like toxin type II operons. Microb Pathog 15:77–82. [PubMed][CrossRef]
138. Persson S, Olsen KE, Ethelberg S, Scheutz F. 2007. Subtyping method for Escherichia coli Shiga toxin (verocytotoxin) 2 variants and correlations to clinical manifestations. J Clin Microbiol 45:2020–2024. [PubMed][CrossRef]
139. Weinstein DL, Jackson MP, Samuel JE, Holmes RK, O'Brien AD. 1988. Cloning and sequencing of a Shiga-like toxin type II variant from Escherichia coli strain responsible for edema disease of swine. J Bacteriol 170:4223–4230. [PubMed]
140. Schmidt H, Scheef J, Morabito S, Caprioli A, Wieler LH, Karch H. 2000. A new Shiga toxin 2 variant (Stx2f) from Escherichia coli isolated from pigeons. Appl Environ Microbiol 66:1205–1208. [PubMed][CrossRef]
141. Leung PH, Peiris JS, Ng WW, Robins-Browne RM, Bettelheim KA, Yam WC. 2003. A newly discovered verotoxin variant, VT2g, produced by bovine verocytotoxigenic Escherichia coli. Appl Environ Microbiol 69:7549–7553. [PubMed][CrossRef]
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/content/journal/microbiolspec/10.1128/microbiolspec.EHEC-0024-2013
2014-07-31
2017-11-23

Abstract:

Shiga toxin (Stx) is one of the most potent bacterial toxins known. Stx is found in 1 and in some serogroups of (called Stx1 in ). In addition to or instead of Stx1, some strains produce a second type of Stx, Stx2, that has the same mode of action as Stx/Stx1 but is antigenically distinct. Because subtypes of each toxin have been identified, the prototype toxin for each group is now designated Stx1a or Stx2a. The Stxs consist of two major subunits, an A subunit that joins noncovalently to a pentamer of five identical B subunits. The A subunit of the toxin injures the eukaryotic ribosome and halts protein synthesis in target cells. The function of the B pentamer is to bind to the cellular receptor, globotriaosylceramide, Gb3, found primarily on endothelial cells. The Stxs traffic in a retrograde manner within the cell, such that the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum. In humans infected with Stx-producing , the most serious manifestation of the disease, hemolytic-uremic syndrome, is more often associated with strains that produce Stx2a rather than Stx1a, and that relative toxicity is replicated in mice and baboons. Stx1a and Stx2a also exhibit differences in cytotoxicity to various cell types, bind dissimilarly to receptor analogs or mimics, induce differential chemokine responses, and have several distinctive structural characteristics.

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Figures

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FIGURE 1

Cartoon representation of the Stx structure. The active-site glutamic acid is indicated as a vertical blue line, the ribosome interaction region is shown in purple, the protease (furin)- sensitive site is depicted in green, and the B pentamer as an orange block. The disulfide bridge that connects the A subunit and the A peptide is shown above the protease-sensitive site. A region important for translocation from the ER to the cytosol is indicated by a bracket. Not to scale. doi:10.1128/microbiolspec.EHEC-0024-2013.f1

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013
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FIGURE 2

Ribbon diagram of the Stx1 crystal structure. The B pentamer is shown in orange and the A in blue. The majority of the A is depicted in green except for the region that interacts with the ribosome, which is shown in purple. The active residue 167 is red, and other active-site side chains are pale blue. The A chain is medium blue, and the B subunits are orange. The structure (1R4Q) was drawn with PyMOL Molecular Graphics System, Version 1.5.0, Schrödinger, LLC. Figure kindly provided by Dr. James Vergis. doi:10.1128/microbiolspec.EHEC-0024-2013.f2

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013
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FIGURE 3

An illustration of the retrograde pathway for Stxs. The toxin binds to Gb3 within lipid rafts that contain cholesterol and that complex is internalized within an endosome. From the endosome the toxin traffics to the Golgi where it is nicked by furin if that nicking did not occur in the intestine. The nicked toxin moves to the ER where the disulfide bridge that keeps the A tethered to AB5 is reduced. The A chain then enters the cytosol and removes an adenine residue from the 28S ribosome. doi:10.1128/microbiolspec.EHEC-0024-2013.f3

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013
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Tables

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TABLE 1

Prototype toxins and strains that produce those toxins

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013

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