New Aspects in the Pathogenesis of Enteropathic Hemolytic Uremic Syndrome

ABSTRACT

Shiga toxin (Stx) subtyping suggests that the clinical outcome of infections caused by Shiga toxin-producing Escherichia coli (STEC) depends, in large part, on the stx genotype of the infecting strain. Whereas the presence of the stx₂ or stx_2c genotype is associated with the ability of STEC to cause the hemolytic uremic syndrome (HUS), strains possessing stx_2d or stx_2e have been isolated from patients with less severe disease. In addition to the type of Stx, the level of Stx production might be critical for the pathogenicity of STEC. Control of Stx expression appears to be at the level of transcription. Injury to microvascular endothelial cells is the key event underlying the pathogenesis of HUS. We could show that in addition to Stx, STEC also produces other putative virulence factors, such as cytolethal distending toxin, which can contribute to the endothelial injury by interference with the cell cycle, which results in inhibition of cell proliferation and finally cell death.

KEYWORDS

Hemolytic uremic syndrome (HUS) - pathogenesis of HUS - Shiga toxin - children - endothelial cells - endothelial damage

REFERENCES

• 1 Karmali M A. Infection by Shiga toxin-producing Escherichia coli: an overview.  Mol Biotechnol. 2004;  26 117-122
• 2 Tarr P I, Gordon C A, Chandler W L. Shiga toxin-producing Escherichia coli and the haemolytic uraemic syndrome.  Lancet. 2005;  365 1073-1086
• 3 Caprioli A, Morabito S, Brugereb H et al.. Enterohaemorrhagic Escherichia coli: emerging issues on virulence and modes of transmission.  Vet Res. 2005;  36 289-311
• 4 Scotland S M, Smith H R, Rowe B. Two distinct toxins active on Vero cells from Escherichia coli O157:H7.  Lancet. 1985;  2 885-886
• 5 O'Brien A D, Tesh V L, Donohue-Rolfe A et al.. Shiga toxin: biochemistry, genetics, mode of action, and role in pathogenesis.  Curr Top Microbiol Immunol. 1992;  180 65-94
• 6 Sandvig K. Shiga toxins.  Toxicon. 2001;  39 1629-1635
• 7 Zhang W, Bielaszewska M, Kuczius T et al.. Identification, characterization and distribution of a Shiga toxin 1 gene variant (stx_1c ) in Escherichia coli isolated from humans.  J Clin Microbiol. 2002;  40 1441-1446
• 8 Friedrich A W, Borell J, Bielaszewska M et al.. Shiga toxin 1c-producing Escherichia coli strains: phenotypic and genetic characterization and association with human disease.  J Clin Microbiol. 2003;  41 2448-2453
• 9 Bürk C, Dietrich R, Acar G et al.. Identification and characterization of a new variant of Shiga toxin 1 in Escherichia coli ONT:H19 of bovine origin.  J Clin Microbiol. 2003;  41 2106-2112
• 10 Kuczius T, Bielaszewska M, Friedrich A W et al.. A rapid method for the discrimination of genes encoding classical Shiga toxin (Stx) 1 and its variants, Stx1c and Stx1d, in Escherichia coli. .  Mol Nutr Food Res. 2004;  48 515-521
• 11 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
• 12 Jelacic J K, Damrow T, Chen G S et al.. Shiga toxin-producing Escherichia coli in Montana: bacterial genotypes and clinical profiles.  J Infect Dis. 2003;  188 719-729
• 13 Melton-Celsa A R, Darnell S C, O'Brien A D. 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. 1996;  64 1569-1576
• 14 Pierard D, Muyldermas G, Moriau L et al.. Identification of new Verocytotoxin type 2 variant B-subunit genes in human and animal Escherichia coli isolates.  J Clin Microbiol. 1998;  36 3317-3322
• 15 Sonntag A K, Bielaszewska M, Mellmann A et al.. Shiga toxin 2e-producing Escherichia coli from humans and pigs differ by their virulence profiles and interaction with intestinal epithelial cells.  Appl Environ Microbiol. 2005;  71 8855-8863
• 16 Schmidt H, Scheef J, Morabito S et al.. A new Shiga toxin 2 variant (Stx2f) from Escherichia coli isolated from pigeons.  Appl Environ Microbiol. 2000;  66 1205-1208
• 17 Sonntag A-K, Zenner E, Karch H et al.. Pigeons as a possible reservoir of Shiga toxin 2f-producing Escherichia coli pathogenic to humans.  Berl Munch Tierarztl Wochenschr. 2005;  118 464-470
• 18 Beutin L, Krause G, Zimmermann S et al.. Characterization of Shiga toxin-producing Escherichia coli strains isolated from human patients in Germany over a 3-year period.  J Clin Microbiol. 2004;  42 1099-1108
• 19 Staschen B, Friedrich A W, Schröder M et al.. Incidence of enterohemorrhagic Escherichia coli (EHEC) in hospitalized children with diarrhea in northern Germany.  Monatsschrift Kinderheilkunde. 2004;  152 1077-1083
• 20 Kehl K S, Havens P, Behnke C E et al.. Evaluation of the premier EHEC assay for detection of Shiga toxin-producing Escherichia coli .  J Clin Microbiol. 1997;  35 2051-2054
• 21 Karmali M A, Petric M, Bielaszewska M. Evaluation of a microplate latex agglutination method (Verotox-F) for detecting and characterizing verotoxins (Shiga toxins) in Escherichia coli .  J Clin Microbiol. 1999;  37 396-399
• 22 Zhang W, Bielaszewska M, Friedrich A W et al.. Transcriptional analysis of genes encoding Shiga toxin 2 and its variants in Escherichia coli. .  Appl Environ Microbiol. 2005;  71 558-561
• 23 Friedrich A W, Bielaszewska M, Zhang W L et al.. Escherichia coli harboring Shiga toxin 2 gene variants: frequency and association with clinical symptoms.  J Infect Dis. 2002;  185 74-84
• 24 Kusumoto M, Nishiya Y, Kawamura Y et al.. Identification of an insertion sequence, IS1203 variant, in a Shiga toxin 2 gene of Escherichia coli O145:H7.  J Biosci Bioeng. 1999;  87 93-96
• 25 Reischl U, Youssef M T, Kilwinski J et al.. Real-time fluorescence PCR assays for detection and characterization of Shiga toxin, intimin, and enterohemolysin genes from Shiga toxin-producing Escherichia coli. .  J Clin Microbiol. 2002;  40 2555-2565
• 26 Pulz M, Matussek A, Monazahian M et al.. Comparison of a Shiga toxin enzyme-linked immunosorbent assay and two types of PCR for detection of shiga toxin-producing Escherichia coli in human stool specimens.  J Clin Microbiol. 2003;  41 4671-4675
• 27 Mellmann A, Bielaszewska M, Zimmerhackl L B et al.. Enterohemorrhagic Escherichia coli in human infection: in vivo evolution of a bacterial pathogen.  Clin Infect Dis. 2005;  41 785-792
• 28 Janka A, Bielaszewska M, Dobrindt U et al.. Identification and distribution of the enterohemorrhagic Escherichia coli factor for adherence (efa1) gene in sorbitol-fermenting Escherichia coli O157:H^- .  Int J Med Microbiol. 2002;  292 207-214
• 29 Janka A, Bielaszewska M, Dobrindt U et al.. The cytolethal distending toxin (cdt) gene cluster in enterohemorrhagic Escherichia coli O157:H^- and O157:H7: characterization and evolutionary considerations.  Infect Immun. 2003;  71 3634-3638
• 30 Janka A, Becker G, Sonntag A-K et al.. Presence and characterization of a mosaic genomic island which distinguishes sorbitol-fermenting enterohemorrhagic Escherichia coli O157:H^- from E. coli O157:H7.  Appl Environ Microbiol. 2005;  71 4875-4878
• 31 Dobrindt U, Agerer F, Michaelis K et al.. Analysis of genome plasticity in pathogenic and commensal Escherichia coli isolates by use of DNA arrays.  J Bacteriol. 2003;  185 1831-1840
• 32 Oswald E, Schmidt H, Morabito S et al.. Typing of intimin genes in human and animal enterohemorrhagic and enteropathogenic Escherichia coli: characterization of a new intimin variant.  Infect Immun. 2000;  68 64-71
• 33 Zhang W-L, Köhler B, Oswald E et al.. Genetic diversity of intimin genes of attaching and effacing Escherichia coli strains.  J Clin Microbiol. 2002;  40 4486-4492
• 34 Nataro J P, Kaper J B. Diarrheagenic Escherichia coli. .  Clin Microbiol Rev. 1998;  11 142-201
• 35 Tarr P I, Bilge S S, Vary J C et al.. 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
• 36 Nicholls L, Grant T H, Robins-Browne R M. Identification of a novel genetic locus that is required for in vitro adhesion of a clinical isolate of enterohaemorrhagic Escherichia coli to epithelial cells.  Mol Microbiol. 2000;  35 275-288
• 37 Paton A W, Srimanote P, Woodrow M C et al.. Characterization of Saa, a novel autoagglutinating adhesin produced by locus of enterocyte effacement-negative Shiga-toxigenic Escherichia coli strains that are virulent for humans.  Infect Immun. 2001;  69 6999-7009
• 38 Friedrich A W, Nierhoff K V, Bielaszewska M et al.. Phylogeny, clinical associations, and diagnostic utility of the pilin subunit gene (sfpA) of sorbitol-fermenting, enterohemorrhagic Escherichia coli O157:H^- .  J Clin Microbiol. 2004;  42 4697-4701
• 39 Doughty S, Sloan J, Bennett-Wood V et al.. Identification of a novel fimbrial gene cluster related to long polar fimbriae in locus of enterocyte effacement-negative strains of enterohemorrhagic Escherichia coli. .  Infect Immun. 2002;  70 6761-6769
• 40 Karmali M A, Mascarenhas M, Shen S et al.. Association of genomic O island 122 of Escherichia coli EDL 933 with verocytotoxin-producing Escherichia coli seropathotypes that are linked to epidemic and/or serious disease.  J Clin Microbiol. 2003;  41 4930-4940
• 41 Jores J, Wagner S, Rumer L et al.. Description of a 111-kb pathogenicity island (PAI) encoding various virulence features in the enterohemorrhagic E. coli (EHEC) strain RW1374 (O103:H2) and detection of a similar PAI in other EHEC strains of serotype 0103:H2.  Int J Med Microbiol. 2005;  294 417-425
• 42 Lathem W W, Grys T E, Witowski S E et al.. StcE, a metalloprotease secreted by Escherichia coli O157:H7, specifically cleaves C1 esterase inhibitor.  Mol Microbiol. 2002;  45 277-288
• 43 Paton A W, Srimanote P, Talbot U M et al.. A new family of potent AB₅ cytotoxins produced by Shiga toxigenic Escherichia coli. .  J Exp Med. 2004;  200 35-46
• 44 Bielaszewska M, Fell M, Greune L et al.. Characterization of cytolethal distending toxin genes and expression in Shiga toxin-producing Escherichia coli strains of non-O157 serogroups.  Infect Immun. 2004;  72 1812-1816
• 45 Bielaszewska M, Sinha B, Kuczius T et al.. Cytolethal distending toxin from Shiga toxin-producing Escherichia coli O157 causes irreversible G2/M arrest, inhibition of proliferation and death of human endothelial cells.  Infect Immun. 2005;  73 552-562
• 46 Bielaszewska M, Zhang W, Tarr P I et al.. Molecular profiling and phenotype analysis of Escherichia coli O26:H11 and O26:NM: secular and geographic consistency of enterohemorrhagic and enteropathogenic isolates.  J Clin Microbiol. 2005;  43 4225-4228
• 47 Bielaszewska M, Tarr P I, Karch H et al.. Phenotypic and molecular analysis of tellurite resistance among enterohemorrhagic Escherichia coli O157:H7 and sorbitol-fermenting O157:NM clinical isolates.  J Clin Microbiol. 2005;  43 452-454
• 48 Friedrich A W, Köck R, Bielaszewska M et al.. Distribution of the urease gene cluster among and urease activities of enterohemorrhagic Escherichia coli O157 isolates from humans.  J Clin Microbiol. 2005;  43 546-550
• 49 Thelestam M, Frisan T. Cytolethal distending toxins.  Rev Physiol Biochem Pharmacol. 2004;  152 111-133
• 50 Cortes-Bratti X, Frisan T, Thelestam M. The cytolethal distending toxins induce DNA damage and cell cycle arrest.  Toxicon. 2001;  39 1729-1736
• 51 Scott D A, Kaper J B. Cloning and sequencing of the genes encoding Escherichia coli cytolethal distending toxin.  Infect Immun. 1994;  62 244-251
• 52 Pickett C L, Cottle D L, Pesci E C et al.. Cloning, sequencing, and expression of the Escherichia coli cytolethal distending toxin genes.  Infect Immun. 1994;  62 1046-1051
• 53 Peres S Y, Marches O, Daigle F et al.. A new cytolethal distending toxin (CDT) from Escherichia coli producing CNF2 blocks HeLa cell division in G2/M phase.  Mol Microbiol. 1997;  24 1095-1107
• 54 Elwell C A, Dreyfus L A. DNase I homologous residues in CdtB are critical for cytolethal distending toxin-mediated cell cycle arrest.  Mol Microbiol. 2000;  37 952-963
• 55 Lara-Tejero M, Galan J E. A bacterial toxin that controls cell cycle progression as a deoxyribonuclease I-like protein.  Science. 2000;  290 354-357
• 56 Lara-Tejero M, Galan J E. CdtA, CdtB, and CdtC form a tripartite complex that is required for cytolethal distending toxin activity.  Infect Immun. 2001;  69 4358-4365
• 57 Deng K, Hansen E JA. CdtA-CdtC complex can block killing of HeLa cells by Haemophilus ducreyi cytolethal distending toxin.  Infect Immun. 2003;  71 6633-6640
• 58 Toth I, Herault F, Beutin L et al.. Production of cytolethal distending toxins by pathogenic Escherichia coli isolated from human and animal sources: Establishment of the existence of a new cdt variant (type IV).  J Clin Microbiol. 2003;  41 4285-4291
• 59 Prager R, Annemuller S, Tschäpe H. Diversity of virulence patterns among shiga toxin-producing Escherichia coli from human clinical cases-need for more detailed diagnostics.  Int J Med Microbiol. 2005;  295 29-38
• 60 Pickett C L, Lee R B, Eyigor A et al.. Patterns of variations in Escherichia coli strains that produce cytolethal distending toxin.  Infect Immun. 2004;  72 684-690
• 61 Richardson S E, Karmali M A, Becker L E et al.. The histopathology of the hemolytic uremic syndrome associated with verocytotoxin-producing Escherichia coli infections.  Hum Pathol. 1988;  19 1102-1108
• 62 Matussek A, Lauber J, Bergau A et al.. Molecular and functional analysis of Shiga toxin-induced response patterns in human vascular endothelial cells.  Blood. 2003;  102 1323-1332
• 63 Gerber A, Karch H, Allerberger F et al.. Clinical course and the role of Shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997-2000, in Germany and Austria: a prospective study.  J Infect Dis. 2002;  186 493-500
• 64 Sonntag A, Prager R, Bielaszewska M et al.. Phenotypic and genotypic analyses of enterohemorrhagic Escherichia coli O145 strains from patients in Germany.  J Clin Microbiol. 2004;  42 954-962
• 65 Misselwitz J, Karch H, Bielazewska M et al.. Cluster of hemolytic-uremic syndrome caused by Shiga toxin-producing Escherichia coli O26:H11.  J Pediatr Infect Dis J. 2003;  22 349-354