New Aspects in the Pathogenesis of Enteropathic Hemolytic Uremic Syndrome

Helge Karch; Alexander W. Friedrich; Angela Gerber; Lothar B. Zimmerhackl; M. Alexander Schmidt; Martina Bielaszewska

doi:10.1055/s-2006-939766

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2006; 32(2): 105-112
DOI: 10.1055/s-2006-939766

New Aspects in the Pathogenesis of Enteropathic Hemolytic Uremic Syndrome

Helge Karch¹ , Alexander W. Friedrich¹ , Angela Gerber² , Lothar B. Zimmerhackl³ , M. Alexander Schmidt⁴ , Martina Bielaszewska¹

¹Institut für Hygiene und Konsiliarlaboratorium für Hämolytisch-Urämisches Syndrom, Universitätsklinikum Münster, Münster, Germany
²Zentrum für Kinderheilkunde und Jugendmedizin, Universität Freiburg, Freiburg, Germany
³Universitätsklinik für Kinder- und Jugendmedizin, Universität Innsbruck, Innsbruck, Austria
⁴Institut für Infektiologie, Zentrum für Molekularbiologie der Entzündung, Universitätsklinikum Münster, Münster, Germany

Abstract

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

Full Text

References

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

Helge KarchPh.D.

Professor, Institut für Hygiene, Universitätsklinikum Münster

Robert-Koch-Str. 41, D-48149 Münster, Germany

Email: hkarch@uni-muenster.de