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Semin Thromb Hemost 2001; 27(3): 207-214
DOI: 10.1055/s-2001-15250
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

The Role of Virulence Factors in Enterohemorrhagic Escherichia coli (EHEC) - Associated Hemolytic-Uremic Syndrome

Helge Karch
  • Institut für Hygiene, Universität Münster, Münster, Germany
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Publication History

Publication Date:
31 December 2001 (online)

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ABSTRACT

Enterohemorrhagic Escherichia coli (EHEC) are the most common cause of postdiarrheal hemolytic-uremic syndrome (HUS). The most important EHEC serotype implicated worldwide is O157:H7. However, several so-called non-O157 EHEC serotypes have emerged. After a mean incubation period of 3 days, patients develop watery diarrhea accompanied by cramping abdominal pain. During the next days, in most patients watery diarrhea changes to bloody diarrhea. One week after the onset of diarrhea, in about 15% of infected patients under 10 years of age EHEC infection results in a systemic complication, HUS. Shiga toxins (Stxs) are considered the major virulence factors of EHEC involved in the pathogenesis of HUS. It is generally believed that after intestinal infection with EHEC, Stxs cross the intestinal barrier and bind to endothelial cells. At this point they presumably injure the host cell by inhibition of protein synthesis, stimulation of prothrombotic messages, or induction of apoptosis. The B subunit of Stx binds to the membrane receptor globotriaosylceramide (Gb3). Gb3 facilitates the endocytosis and intracellular trafficking of the toxin. The Stx A subunit hydrolyzes a specific adenine residue of the 60S ribosomal subunit of mammalian cells. As a consequence, Stx shuts down the protein machinery of the susceptible cell. The HUS is the net effect of a variety of interacting factors, including background risk of acquisition, host factors (such as age), virulence characteristics of the infecting EHEC strain, and exogenous factors. All known EHEC virulence determinants are located on mobile genetic elements, and this has an important impact on the evolution of these pathogens. The evolution of EHEC has a dynamic component that includes different genetic mechanisms. The recent progress in understanding the pathogenesis and epidemiology of EHEC infections forms a basis for the development of future strategies to prevent EHEC infections in humans.

KEYWORD

Hemolytic-uremic syndrome - HUS - Escherichia coli - E. coli O157 - epidemiology - Shiga toxins - enterohemorrhagic E. coli

REFERENCES

  • 1 Kaplan B S. The pathogenesis and treatment of hemolytic uremic syndrome.  J Am Soc Nephrol . 1998;  9 1126-1133
    PubMedGoogle Scholar
  • 2 Bockemühl J, Karch H. Zur aktuellen Bedeutung der enterohämorrhagischen Escherichia coli (EHEC) in Deutschland (1994-1995).  Bundesgesundheitsblatt . 1996;  8 290-296
    PubMedGoogle Scholar
  • 3 Bockemühl J, Karch H, Tschäpe H. Infektionen des Menschen durch enterohämorrhagische Escherichia coli (EHEC) in Deutschland, 1996.  Bundesgesundheitsblatt . 1997;  6 194-197
    PubMedGoogle Scholar
  • 4 Bockemühl J, Karch H, Tschäpe H. Zur Situation der Infektionen des Menschen durch enterohämorrhagische Escherichia coli (EHEC) in Deutschland, 1997.  Bundesgesundheitsblatt . 1998;  Suppl(October) 2-5
    PubMedGoogle Scholar
  • 5 Tarr P I. Escherichia coli O157:H7: clinical, diagnostic, and epidemiological aspects of human infection.  Clin Infect Dis . 1995;  20 1-8
    PubMedGoogle Scholar
  • 6 Karch H, Bielaszewska M, Bitzan M, Schmidt H. Epidemiology and diagnosis of Shiga toxin-producing Escherichia coli infections.  Diagn Microbiol Infect Dis . 1999;  34 229-243
    CrossrefPubMedGoogle Scholar
  • 7 Caprioli A, Tozzi A E, Rizzoni G, Karch H. Non-O157 Shiga toxin-producing Escherichia coli infections in Europe.  Emerg Infect Dis . 1997;  3 578-579
    CrossrefPubMedGoogle Scholar
  • 8 Caprioli A, Tozzi A E. Epidemiology of Shiga toxin-producing Escherichia coli infections in continental Europe. In: Kaper JB, O'Brien AD, eds. Escherichia coli O157:H7 and other Shiga Toxin-Producing Ecoli Strains. Washington, DC: American Society for Microbiology 1998: 38-48
    Google Scholar
  • 9 Acheson D WK, Keusch G T. Which Shiga toxin-producing types of Ecoliare important?.  ASM News. 1995;  62 302-306
    PubMedGoogle Scholar
  • 10 Acheson D WK, Wolf L E, Park C H. Escherichia coli and the hemolytic uremic syndrome.  N Engl J Med . 1997;  336 515
    CrossrefPubMedGoogle Scholar
  • 11 Park C H, Gates K M, Vandel N M, Hixon D L. Isolation of Shiga-like toxin producing Escherichia coli (O157 and non-O157) in a community hospital.  Diagn Microbiol Infect Dis . 1996;  26 69-72
    CrossrefPubMedGoogle Scholar
  • 12 Lopez E L, Diaz M, Grinstein S. Hemolytic uremic syndrome and diarrhoea in Argentine children: the role of Shiga-like toxins.  J Infect Dis . 1989;  160 469-475
    PubMedGoogle Scholar
  • 13 Goldwater P N, Bettelheim K A. The role of enterohaemorrhagic Escherichia coli serotypes other than O157:H7 as causes of disease.  Commun Dis Intell . 1995;  19 2-4
    PubMedGoogle Scholar
  • 14 Gunzer F, Böhm H, Rüssmann H. Molecular detection of sorbitol-fermenting Escherichia coli O157 in patients with hemolytic-uremic syndrome.  J Clin Microbiol . 1992;  30 1807-1810
    PubMedGoogle Scholar
  • 15 Bielaszewska M, Schmidt H, Karmali M A. Isolation and characterization of sorbitol-fermenting Shiga toxin-producing Escherichia coli O157:H- strains in the Czech Republic.  J Clin Microbiol . 1998;  36 2135-2137
    PubMedGoogle Scholar
  • 16 O'Brien A D, Newland J W, Miller S F. Shiga-like toxin converting bacteriophages from Escherichia coli strains that cause hemorrhagic colitis or infantile diarrhea.  Science . 1984;  226 694-696
    PubMedGoogle Scholar
  • 17 Smith H W, Green P, Parsell Z. Vero cell toxin in Escherichia coli and related bacteria: transfer by phage and conjugation and toxic action in laboratory animals, chicken and pigs.  J Gen Microbiol . 1983;  129 3121-3137
    PubMedGoogle Scholar
  • 18 Kaper J B, Elliott S, Sperandio V. Attaching-and-effacing intestinal histopathology and the locus of enterocyte effacement. In: Kaper JB, O'Brien AD, eds. Escherichia coli O157:H7 and other Shiga Toxin-Producing Ecoli Strains. Washington, DC: American Society for Microbiology 1998: 163-182
    Google Scholar
  • 19 Karch H, Schubert S, Zhang D. A genomic island, termed ``high pathogenicity island'', is present in certain non-O157 Shiga toxin-producing Escherichia coli clonal lineages.  Infect Immun . 1999;  68 5994-6001
    PubMedGoogle Scholar
  • 20 Tarr P I, Bilge S S, Vary J C. Iha: a novel Escherichia coli O157:H7 adherence-conferring molecule encoded on a recently acquired chromosomal island of conserved structure.  Infect Immun . 2000;  68 1400-1407
    CrossrefPubMedGoogle Scholar
  • 21 Karch H, Schmidt H, Brunder W. Plasmid-encoded determinants of Escherichia coli O157:H7. In: Kaper JB, O'Brien AD, eds. Escherichia coli O157:H7 and other Shiga Toxin-Producing Ecoli Strains. Washington, DC: American Society for Microbiology 1998: 183-194
    Google Scholar
  • 22 Brunder W, Schmidt H, Frosch M, Karch H. The large plasmids of Shiga-toxin-producing Escherichia coli (STEC) are highly variable genetic elements.  Microbiology . 1999;  145 1005-1014
    PubMedGoogle Scholar
  • 23 O'Brien A D, Tesh V L, Donohue R A. Shiga toxin: biochemistry, genetics, mode of action, and role in pathogenesis.  Curr Top Microbiol Immunol . 1992;  180 65-94
    PubMedGoogle Scholar
  • 24 Schmitt C K, McKee M L, O'Brien A D. 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 . 1991;  59 1065-1073
    PubMedGoogle Scholar
  • 25 Pierard D, Muyldermas G, Moriau L, Stevens D, Lauwers S. Identification of new verocytotoxin type 2 variant B-subunit genes in human and animal Escherichia coli isolates.  J Clin Microbiol . 1998;  36 3317-3322
    PubMedGoogle Scholar
  • 26 Weinstein D L, Jackson M P, Samuel J E, Holmes R K, O'Brien A D. Cloning and sequencing of a Shiga-like toxin type II variant from an Escherichia coli strain responsible for edema disease of swine.  J Bacteriol . 1988;  170 4223-4230
    PubMedGoogle Scholar
  • 27 Schmidt H, Scheef J, Morabito S. A new Shiga toxin variant (Stx2f) from Escherichia coli isolated from pigeons.  Appl Environ Microbiol . 2000;  66 1205-1208
    CrossrefPubMedGoogle Scholar
  • 28 Rüssmann H, Schmidt H, Heesemann J, Caprioli A, Karch H. Variants of Shiga-like toxin II constitute a major toxin component in Escherichia coli O157 strains from patients with haemolytic uraemic syndrome.  J Med Microbiol . 1994;  40 338-343
    PubMedGoogle Scholar
  • 29 Karch H. Unpublished data, 2000 . 
    Google Scholar
  • 30 Karmali M A, Petric M, Lim C. The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli J Infect Dis .  1985;  151 775-782
    PubMedGoogle Scholar
  • 31 Richardson S E, Rotman T A, Jay V. Experimental verocytotoxemia in rabbits.  Infect Immun . 1992;  60 4154-4167
    PubMedGoogle Scholar
  • 32 Hertzke D M, Cowan L A, Schoning P, Fenwick B W. Glomerular ultrastructural lesions of idiopathic cutaneous and renal glomerular vasculopathy of greyhounds.  Vet Pathol . 1995;  32 451-459
    CrossrefPubMedGoogle Scholar
  • 33 Taylor F B, Tesh V L, DeBault L. Characterization of the baboon responses to Shiga-like toxin: descriptive study of a new primate model of toxic responses to Stx-1.  Am J Pathol . 1999;  154 1285-1299
    CrossrefPubMedGoogle Scholar
  • 34 Mangeney M, Lingwood C A, Taga S. Apoptosis induced in Burkitt's lymphoma cells via Gb3/CD77, a glycolipid antigen.  Cancer Res . 1993;  53 5314-5319
    PubMedGoogle Scholar
  • 35 Taga S, Carlier K, Mishal Z. Intracellular signaling events in CD77-mediated apoptosis of Burkitt's lymphoma cells.  Blood . 1997;  90 2757-2767
    PubMedGoogle Scholar
  • 36 Nagakawa I, Nakata M, Kawabata S, Hamada S. Regulated expression of the Shiga toxin B gene induces apoptosis in mammalian fibroblastic cells.  Mol Microbiol . 1999;  33 1190-1199
    CrossrefPubMedGoogle Scholar
  • 37 van Setten A P, van Hinsberg W V>, van-der Velden J T. Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells.  Kidney Int . 1997;  51 1245-1256
    CrossrefPubMedGoogle Scholar
  • 38 Louise B, Obrig T G. Specific interaction of Escherichia coli O157:H7-derived Shiga-like toxin II with human renal endothelial cells.  J Infect Dis . 1995;  172 1397-1401
    PubMedGoogle Scholar
  • 39 Bombeli T, Schwartz B R, Harlan J M. Endothelial cells undergoing apoptosis become proadhesive for nonactivated platelets.  Blood . 1999;  93 3831-3838
    PubMedGoogle Scholar
  • 40 Taguchi T, Uchida H, Kiyokawa N. Verotoxins induce apoptosis in human renal tubular epithelium derived cells.  Kidney Int . 1998;  53 1681-1688
    CrossrefPubMedGoogle Scholar
  • 41 Uchida H, Kiyokawa N, Taguchi T. Shiga toxins induce apoptosis in pulmonary epithelium-derived cells.  J Infect Dis . 1999;  180 1902-1911
    CrossrefPubMedGoogle Scholar
  • 42 Hughes A K, Stricklett P K, Kohan D E. Shiga toxin 1 regulation of cytokine production by human proximal tubule cells.  Kidney Int . 1998;  54 1093-1106
    CrossrefPubMedGoogle Scholar
  • 43 Simon M, Cleary T G, Hernandez J D, Abboud H E. Shiga toxin 1 elicits diverse biologic responses in mesangial cells.  Kidney Int . 1998;  54 1117-1127
    CrossrefPubMedGoogle Scholar
  • 44 van de Kar C N, Monnens L A, Karmali M A, van Hinsbergh W V. Tumor necrosis factor and interleukin-1 induce expression of the verocytotoxin receptor globotriaosylceramide on human endothelial cells: implications for the pathogenesis of the hemolytic uremic syndrome.  Blood . 1992;  80 2755-2764
    PubMedGoogle Scholar
  • 45 Karpman D, Hakansson A, Perez M T. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: in vivo and in vitro studies.  Infect Immun . 1998;  66 636-644
    PubMedGoogle Scholar
  • 46 Bitzan M, Marsden P A. Novel effects of verotoxin on intracellular adhesion molecule-1 gene expression in vascular endothelium.  Pediatr Nephrol (Abst). 1998;  12 C74
    PubMedGoogle Scholar
  • 47 Kimmitt P T, Hardwood C R, Barer M R. Toxin gene expression by Shiga toxin-producing Escherichia coli: the role of antibiotics and the bacterial SOS response.  Emerg Infect Dis . 2000;  6 1-11
    PubMedGoogle Scholar
  • 48 Neely M N, Friedman D I. Functional and genetic analysis of regulatory regions of coliphage H-19: location of Shiga-like toxin and lysis genes suggest a role for phage functions in toxin release.  Mol Microbiol . 1998;  28 1255-1267
    CrossrefPubMedGoogle Scholar
  • 49 Plunkett III G, Rose D J, Durfee T J, Blattner F R. Sequence of Shiga toxin 2 phage 933W from Escherichia coli O157:H7: Shiga toxin as a phage late-gene product.  J Bacteriol . 1999;  181 1767-1778
    PubMedGoogle Scholar
  • 50 Karch H, Strockbine N A, O'Brien A D. Growth of Escherichia coli in the presence of trimethoprim-sulfamethoxazole facilitates detection of Shiga-like toxin producing strains by colony blot assay.  FEMS Microbiol Lett . 1986;  35 141-145
    CrossrefPubMedGoogle Scholar
  • 51 Matsushiro A, Sato K, Miyamoto H, Yamamura T, Honda T. Induction of prophages of enterohemorrhagic Escherichia coli O157:H7 with norfloxacin.  J Bacteriol . 1999;  181 2257-2260
    PubMedGoogle Scholar
  • 52 Wong C S, Jelacic S, Habeeb R, Watkins S, Tarr P. The risk of hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections.  N Engl J Med . 2000;  342 1930-1936
    CrossrefPubMedGoogle Scholar
  • 53 Sherman P, Soni R, Karmali M. Attaching and effacing adherence of Vero cytotoxin-producing Escherichia coli to rabbit intestinal epithelium in vivo.  Infect Immun . 1988;  56 756-761
    PubMedGoogle Scholar
  • 54 Frankel G, Phillips A D, Rosenshine I. Enteropathogenic and enterohemorrhagic Escherichia coli: more submersive elements.  Mol Microbiol . 1998;  30 911-921
    CrossrefPubMedGoogle Scholar
  • 55 Hurley B P, Jacewicz M, Thorpe C M. Shiga toxins 1 and 2 translocate differently across polarized intestinal epithelial cells.  Infect Immun . 1999;  67 6670-6677
    PubMedGoogle Scholar
  • 56 Paton A W, Manning P A, Woodrow M C, Paton J C. Translocated intimin receptors (Tir) of Shiga-toxigenic Escherichia coli isolates belonging to serogroups O26, O111, and O157 react with sera from patients with hemolytic-uremic syndrome and exhibit marked heterogeneity.  Infect Immun . 1998;  66 5580-5586
    PubMedGoogle Scholar
  • 57 Jarvis K, Kaper J B. Secretion of extracellular proteins by enterohemorrhagic Escherichia coli via putative type III secretion system.  Infect Immun . 1996;  64 4826-4829
    PubMedGoogle Scholar
  • 58 Carniel I, Guilvout I, Prentice M. Characterization of a large chromosomal ``high pathogenicity island'' in biotype 1B Yersinia enterocolitica J Bacteriol .  1996;  178 6743-6751
    PubMedGoogle Scholar
  • 59 Schmidt H, Beutin L, Karch H. Molecular analysis of the plasmid-encoded hemolysin of Escherichia coli O157:H7 strain EDL 933.  Infect Immun . 1995;  63 1055-1061
    PubMedGoogle Scholar
  • 60 Schmidt H, Maier E, Karch H, Benz R. Pore-forming properties of the plasmid-encoded hemolysin of enterohemorrhagic Escherichia coli O157:H7.  Eur J Biochem . 1996;  241 594-601
    CrossrefPubMedGoogle Scholar
  • 61 Brunder W, Schmidt H, Karch H. KatP, a novel catalase-peroxidase encoded by the large plasmid of enterohemorrhagic Escherichia coli O157:H.  Microbiology . 1996;  142 3305-3315
    PubMedGoogle Scholar
  • 62 Brunder W, Schmidt H, Karch H. EspP, a novel extracellular serine protease of enterohaemorrhagic Escherichia coli O157:H7 cleaves human coagulation factor V.  Mol Microbiol . 1997;  24 767-778
    CrossrefPubMedGoogle Scholar
  • 63 Schmidt H, Henkel B, Karch H. A gene cluster closely related to type II secretion pathway operons of gram-negative bacteria is located on the large plasmid of enterohaemorrhagic Escherichia coli O157 strains.  FEMS Microbiol Lett . 1997;  148 265-272
    CrossrefPubMedGoogle Scholar
  • 64 Burland V, Shao Y, Perna N T. The complete DNA sequence and analysis of the large virulence plasmid of Escherichia coli O157:H7.  Nucleic Acids Res . 1998;  26 4196-4204
    CrossrefPubMedGoogle Scholar
  • 65 Makino K, Ishii K, Yasunaga T. Complete nucleotide sequence of 93-kb and 3.3-kb plasmids of an enterohemorrhagic Escherichia coli O157:H7 derived from Sakai outbreak.  DNA Res . 1998;  5 1-9
    PubMedGoogle Scholar
  • 66 Hughes A K, Stricklett P K, Kohan D E. Cytotoxic effect of Shiga toxin 1 on human proximal tubule cells.  Kidney Int . 1998;  54 426-437
    CrossrefPubMedGoogle Scholar
  • 67 Hughes A K, Stricklett P K, Schmid D, Kohan D E. Cytotoxic effect of Shiga toxin 1 on human glomerular epithelial cells.  Kidney Int . 2000;  57 2350-2359
    CrossrefPubMedGoogle Scholar
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