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Thromb Haemost 2009; 101(02): 252-264
DOI: 10.1160/TH08-05-0317
Theme Issue Article
Schattauer GmbH

Shiga toxins, glycosphingolipid diversity, and endothelial cell injury

Johannes Müthing
1   Institute for Hygiene, University Hospital Münster, Münster, Germany
,
Christian H. Schweppe
1   Institute for Hygiene, University Hospital Münster, Münster, Germany
2   Interdisciplinary Center for Clinical Research, Münster, Germany
,
Helge Karch
1   Institute for Hygiene, University Hospital Münster, Münster, Germany
2   Interdisciplinary Center for Clinical Research, Münster, Germany
,
Alexander W. Friedrich
1   Institute for Hygiene, University Hospital Münster, Münster, Germany
2   Interdisciplinary Center for Clinical Research, Münster, Germany
› Author AffiliationsFinancial support: We are thankful for continuous support of our work by grants from the Deutsche Forschungsgemeinschaft (DFG), SPP 1130 project KA 717/4–2 (H.K.), SFB 293 project A18 (H.K.), the cooperative projects FR2569/1–1 (A.W.F.) and MU845/4–1 (J.M.), the GRK 1409/1 and grants from the Interdisciplinary Center of Clinical Research (IZKF)
Further Information

Publication History

Received: 23 May 2008

Accepted after minor revision: 09 January 2008

Publication Date:
23 November 2017 (online)

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Summary

Shiga toxin (Stx)-producing Escherichia coli (STEC) cause an enteric illness that results in a spectrum of outcomes ranging from asymptomatic carriage to uncomplicated diarrhea, bloody diarrhea, and the postdiarrheal haemolytic uremic syndrome (HUS), which leads to renal and other organ microvascular thrombosis. Binding of Stx to the glycosphingolipid (GSL) globotriaosylceramide (Gb3Cer/CD77) on endothelial cells followed by receptor-mediated endocytosis is the linchpin in STEC-mediated disease. Only GSLs that associate strongly with lipid rafts appear to carry Stxs retrogradely from the plasma membrane through the Golgi apparatus to the endoplasmic reticulum where they are translocated to the cytosol and exert their toxic function. Thus, the biophysical features of the lipid moiety of GSL receptors may influence its incorporation into certain membrane domains and thereby affect toxin destination. Consequently, a detailed structural analysis of Stx-binding GSLs is required to illuminate the molecular causes that may underlie the different Stx susceptibilities of endothelial cells derived from various vascular beds. Solid phase overlay binding assays of thin-layer chromatography (TLC)-separated GSL preparations employing specific antibodies and/or Stxs in conjunction with anti-Stx-antibodies are commonly used for the identification of Stx-binding GSLs. Such GSL-profiling combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) represents a convenient strategy to structurally characterize Stx-receptors from any biological sources such as primary cells, cell lines, or organs. This approach may be helpful to gain insights into Stx-induced impairment of target cells that is suggested to originate at least partly from the structural heterogeneity of the cellular ligands of Stxs.

Keywords

STEC - Gb3Cer - endothelial cells - TLC overlay assay - MALDITOF-MS
 

  • References

  • 1 Karch H. et al. Enterohaemorrhagic Escherichia coli in human medicine. Int J Med Microbiol 2005; 295: 405-418.
    CrossrefPubMedGoogle Scholar
  • 2 Karmali MA. Infection by Shiga toxin-producing Escherichia coli: an overview. Mol Biotechnol 2004; 26: 117-122.
    CrossrefPubMedGoogle Scholar
  • 3 Tarr PI. et al. Shiga toxin-producing Escherichia coli and the haemolytic uraemic syndrome. Lancet 2005; 365: 1073-1086.
    PubMedGoogle Scholar
  • 4 Bielaszewska M, Karch H. Consequences of enterohaemorrhagic Escherichia coli infection for the vascular endothelium. Thromb Haemost 2005; 94: 312-318.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Barbieri L. et al. Shiga-like toxin I is a polynucleotide:adenosine glycosidase. Mol Microbiol 1998; 29: 661-662.
    CrossrefPubMedGoogle Scholar
  • 6 Brigotti M. et al. Damage to nuclear DNA induced by Shiga toxin 1 and ricin in human endothelial cells. FASEB J 2002; 16: 365-372.
    CrossrefPubMedGoogle Scholar
  • 7 Sandvig K. Shiga toxins. Toxicon 2001; 39: 1629-1635.
    CrossrefPubMedGoogle Scholar
  • 8 Jackson MP. et al. Nucleotide sequence analysis and comparison of the structural genes for Shiga-like toxin I and Shiga-like toxin II encoded by bacteriophages from Escherichia coli 933. FEMS Microbiol Lett 1987; 44: 109-114.
    CrossrefPubMedGoogle Scholar
  • 9 Friedrich AW. et al. Escherichia coli harboring Shiga toxin 2 gene variants: frequency and association with clinical symptoms. J Infect Dis 2002; 185: 74-84.
    CrossrefPubMedGoogle Scholar
  • 10 Friedrich AW. 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.
    CrossrefPubMedGoogle Scholar
  • 11 Bielaszewska M. et al. Shiga toxin activatable by intestinal mucus in Escherichia coli isolated from humans: predictor for a severe clinical outcome. Clin Infect Dis 2006; 43: 1160-1167.
    CrossrefPubMedGoogle Scholar
  • 12 Zhang W. et al. Structural and functional differences between disease-associated genes of enterohaemorrhagic Escherichia coli O111. Int J Med Micro-biol 2007; 297: 17-26.
    CrossrefPubMedGoogle Scholar
  • 13 Orth D. et al. The Shiga toxin genotype rather than the amount of Shiga toxin or the cytotoxicity of Shiga toxin in vitro correlates with the appearance of the hemolytic uremic syndrome. Diagn Microbiol Infect Dis 2007; 59: 235-242.
    CrossrefPubMedGoogle Scholar
  • 14 Jenkins C. et al. Subtyping of virulence genes in verocytotoxin-producing Escherichia coli (VTEC) other than serogroup O157 associated with disease in the United Kingdom. J Med Microbiol 2003; 52: 941-947.
    CrossrefPubMedGoogle Scholar
  • 15 Boerlin P. et al. Association between virulence factors of Shiga toxin-producing Escherichia coli and disease in human. J Clin Microbiol 1999; 37: 497-503.
    PubMedGoogle Scholar
  • 16 Beutin L. et al. Characterization of Shiga toxin-producing Escherichia coli strains isolated from humans in Germany over a 3-year period. J Clin Microbiol 2004; 42: 1099-1108.
    CrossrefPubMedGoogle Scholar
  • 17 Brooks JT. et al. Non-O157 Shiga toxin-producing Escherichia coli infections in the United States, 1983–2002. J Infect Dis 2005; 192: 1422-1429.
    CrossrefPubMedGoogle Scholar
  • 18 Zhang W. et al. Identification, characterization and distribution of a Shiga toxin 1 gene variant (stx1c ) in Escherichia coli isolated from humans. J Clin Micro-biol 2002; 40: 1441-1446.
    CrossrefPubMedGoogle Scholar
  • 19 Bürk C. 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.
    CrossrefPubMedGoogle Scholar
  • 20 Kuczius T. 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.
    CrossrefPubMedGoogle Scholar
  • 21 Schmitt CK. et al. 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
  • 22 Jelacic JK. et al. Shiga toxin-producing Escherichia coli in Montana: bacterial genotypes and clinical profiles. J Infect Dis 2003; 188: 719-729.
    CrossrefPubMedGoogle Scholar
  • 23 Pierard D. 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.
    PubMedGoogle Scholar
  • 24 Melton-Celsa AR. et al. 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.
    PubMedGoogle Scholar
  • 25 Sonntag AK. et al. Shiga toxin 2e-producing Escherichia coli isolates from humans and pigs differ in their virulence profiles and interactions with intestinal epithelial cells. Appl Environ Microbiol 2005; 71: 8855-8863.
    CrossrefPubMedGoogle Scholar
  • 26 Sonntag AK. 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.
    PubMedGoogle Scholar
  • 27 Seto K. et al. Biochemical and molecular characterization of minor serogroups of Shiga toxin-producing Escherichia coli isolated from humans in Osaka prefecture. J Vet Med Sci 2007; 69: 1215-1222.
    CrossrefPubMedGoogle Scholar
  • 28 van Duynhoven YT. et al. Prevalence, characterisation and clinical profiles of Shiga toxin-producing Escherichia coli in The Netherlands. Clin Microbiol Infect 2008; 14: 437-445.
    CrossrefPubMedGoogle Scholar
  • 29 Prager R. et al. 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.
    CrossrefPubMedGoogle Scholar
  • 30 Mellmann A. et al. Analysis of the collection of hemolytic uremic syndrome-associated enterohemorrhagic Escherichia coli (HUSEC). Emerg Infect Dis 2008; 14: 1287-1290.
    CrossrefPubMedGoogle Scholar
  • 31 Schmidt H. et al. A new Shiga toxin 2 variant (Stx2f) from Escherichia coli isolated from pigeons. Appl Environ Microbiol 2000; 66: 1205-1208.
    CrossrefPubMedGoogle Scholar
  • 32 Isobe J. et al. Isolation of Escherichia coli O128:HNM harboring stx2f gene from diarrhea patients. Kansenshogaku Zasshi 2004; 78: 1000-1005.
    CrossrefPubMedGoogle Scholar
  • 33 Mellmann A. et al. Recycling of Shiga toxin 2 genes in sorbitol-fermenting enterohemorrhagic Escherichia coli O157:NM. Appl Environ Microbiol 2008; 74: 67-72.
    CrossrefPubMedGoogle Scholar
  • 34 Bielaszewska M. et al. Shiga toxin gene loss and transfer in vitro and in vivo during enterohemorrhagic Escherichia coli O26 infection in humans. Appl Environ Microbiol 2007; 73: 3144-3150.
    CrossrefPubMedGoogle Scholar
  • 35 Bielaszewska M. et al. Shiga toxin-mediated hemolytic uremic syndrome: time to change the diagnostic paradigm?. PLoS ONE 2007; 2: e1024.
    CrossrefPubMedGoogle Scholar
  • 36 Friedrich AW. et al. Prevalence, virulence profiles, and clinical significance of Shiga toxin-negative variants of enterohemorrhagic Escherichia coli O157 infection in humans. Clin Infect Dis 2007; 45: 39-45.
    CrossrefPubMedGoogle Scholar
  • 37 Bielaszewska M. et al. Shiga toxin-negative attaching and effacing Escherichia coli: distinct clinical associations with bacterial phylogeny and virulence traits and inferred in-host pathogen evolution. Clin Infect Dis 2008; 47: 208-217.
    CrossrefPubMedGoogle Scholar
  • 38 Endo Y. et al. Site of action of a Vero toxin (VT2) from Escherichia coli O157:H7 and Shiga toxin on eukaryotic ribosomes. Eur J Biochem 1988; 171: 45-50.
    CrossrefPubMedGoogle Scholar
  • 39 Ling H. et al. Structure of the Shiga-like toxin I B-pentamer complexed with an analogue of its receptor Gb3 . Biochemistry 1998; 37: 1777-1788.
    CrossrefPubMedGoogle Scholar
  • 40 Paton JC, Paton AW. Shiga toxin ‘goes retro’ in human primary kidney cells. Kidney Int 2006; 70: 2049-2051.
    CrossrefPubMedGoogle Scholar
  • 41 Sandvig K. et al. Pathways followed by ricin and Shiga toxin into cells. Histochem Cell Biol 2002; 117: 131-141.
    CrossrefPubMedGoogle Scholar
  • 42 Bonifacino JS, Rojas R. Retrograde transport from endosomes to the trans-Golgi network. Nat Rev Mol Cell Biol 2006; 7: 568-579.
    CrossrefPubMedGoogle Scholar
  • 43 Römer W. et al. Shiga toxin induces tubular membrane invaginations for its uptake into cells. Nature 2007; 450: 670-675.
    CrossrefPubMedGoogle Scholar
  • 44 Sandvig K. et al. Retrograde transport of endocytosed Shiga toxin to the endoplasmic reticulum. Nature 1992; 358: 510-512.
    CrossrefPubMedGoogle Scholar
  • 45 Lingwood CA. Role of verotoxin receptors in pathogenesis. Trends Microbiol 1996; 4: 147-153.
    CrossrefPubMedGoogle Scholar
  • 46 Arab S, Lingwood CA. Intracellular targeting of the endoplasmic reticulum/nuclear envelope by retrograde transport may determine cell hypersensitivity to verotoxin via globotriaosyl ceramide fatty isoform traffic. J Cell Physiol 1998; 177: 646-660.
    CrossrefPubMedGoogle Scholar
  • 47 Garred Ø. et al. Furin-induced cleavage and activation of Shiga toxin. J Biol Chem 1995; 270: 10817-10821.
    CrossrefPubMedGoogle Scholar
  • 48 Lea N. et al. Proteolytic cleavage of the A subunit is essential for maximal cytotoxicity of Escherichia coli O157:H7 Shiga-like toxin-1. Microbiology 1999; 145: 999-1004.
    CrossrefPubMedGoogle Scholar
  • 49 Tam PJ, Lingwood CA. Membrane-cytosolic trans-location of verotoxin A1 subunit in target cells. Microbiology 2007; 153: 2700-2710.
    CrossrefPubMedGoogle Scholar
  • 50 Obrig TG. Shiga toxin mode of action in E. coli O157:H7 disease. Front Biosci 1997; 2: d635-642.
    CrossrefPubMedGoogle Scholar
  • 51 Cherla RP. et al. Shiga toxins and apoptosis. FEMS Microbiol Lett 2003; 228: 159-166.
    CrossrefPubMedGoogle Scholar
  • 52 Nakao H, Takeda T. Escherichia coli Shiga toxin. J Nat Toxins 2000; 9: 299-313.
    PubMedGoogle Scholar
  • 53 Karch H. The role of virulence factors in enterohemorrhagic Escherichia coli (EHEC)-associated hemolytic-uremic syndrome. Semin Thromb Hemost 2001; 27: 207-213.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Forsyth KD. et al. Neutrophil-mediated endothelial injury in haemolytic uraemic syndrome. Lancet 1989; 2: 411-414.
    PubMedGoogle Scholar
  • 55 Morigi M. et al. Verotoxin-1-induced up-regulation of adhesive molecules renders microvascular endothelial cells thrombogenic at high shear stress. Blood 2001; 98: 1828-1835.
    CrossrefPubMedGoogle Scholar
  • 56 Morigi M. et al. Verotoxin-1 promotes leucocyte adhesion to cultured endothelial cells under physiologic flow conditions. Blood 1995; 86: 4553-4558.
    PubMedGoogle Scholar
  • 57 Mulvey G. et al. Affinity purification of Shiga-like toxin I and Shiga-like toxin II. J Microbiol Methods 1998; 32: 247-252.
    CrossrefPubMedGoogle Scholar
  • 58 Nakajima H. et al. Single-step method for purification of Shiga toxin-1 B subunit using receptor-mediated affinity chromatography by globotriaosylceramide-conjugated octyl sepharose CL-4B. Protein Expr Purif 2001; 22: 267-275.
    CrossrefPubMedGoogle Scholar
  • 59 Boulanger J. et al. Universal method for the facile production of glycolipid/lipid matrices for the affinity purification of binding ligands. Anal Biochem 1994; 217: 1-6.
    CrossrefPubMedGoogle Scholar
  • 60 Karch H, Bitzan M. Purification and characterization of a phage-encoded cytotoxin from an Escherichia coli O111 strain associated with hemolyticuremic syndrome. Zentralbl Bakteriol Mikrobiol Hyg 1988; 270: 41-51.
    PubMedGoogle Scholar
  • 61 Karch H. et al. Purified verotoxins of Escherichia coli O157:H7 decrease prostacyclin synthesis by endothelial cells. Microb Pathog 1988; 5: 215-221.
    CrossrefPubMedGoogle Scholar
  • 62 Shevchenko A. et al. Mass spectrometric sequencing of proteins from silver-stained polyacrylamide gels. Anal Chem 1996; 68: 850-858.
    CrossrefPubMedGoogle Scholar
  • 63 Aebersold R, Goodlett DR. Mass spectrometry in proteomics. Chem Rev 2001; 101: 269-295.
    CrossrefPubMedGoogle Scholar
  • 64 Fraser ME. et al. Structure of Shiga toxin type 2 (Stx2) from Escherichia coli O157:H7. J Biol Chem 2004; 279: 27511-27517.
    CrossrefPubMedGoogle Scholar
  • 65 Shayman JA, Radin NS. Structure and function of renal glycosphingolipids. Am J Physiol 1991; 260: F291-302.
    PubMedGoogle Scholar
  • 66 Holgersson J, Jovall PA. Glycosphingolipids of human large intestine: detailed structural characterization with special reference to blood group compounds and bacterial receptor structures. J Biochem 1991; 110: 120-131.
    CrossrefPubMedGoogle Scholar
  • 67 Macher BA. et al. Glycosphingolipids of normal and leukemic human leukocytes. Mol Cell Biochem 1982; 47: 81-95.
    PubMedGoogle Scholar
  • 68 Gillard BK. et al. Association of glycosphingolipids with intermediate filaments of mesenchymal, epithelial, glial, and muscle cells. Cell Motil Cytoskeleton 1992; 21: 255-271.
    CrossrefPubMedGoogle Scholar
  • 69 Feizi T. Carbohydrate differentiation antigens: probable ligands for cell adhesion molecules. Trends Biochem Sci 1991; 16: 84-86.
    CrossrefPubMedGoogle Scholar
  • 70 Erdmann M. et al. Differential surface expression and possible function of 9-O- and 7-O-acetylated GD3 (CD60 b and c) during activation and apoptosis of human tonsillar B and T lymphocytes. Glycoconj J 2006; 23: 627-638.
    CrossrefPubMedGoogle Scholar
  • 71 Alessandri G. et al. Growth and motility of micro-vascular endothelium are modulated by the relative concentration of gangliosides in the medium. J Cell Physiol 1992; 151: 23-28.
    CrossrefPubMedGoogle Scholar
  • 72 Lahiri S, Futerman AH. The metabolism and function of sphingolipids and glycosphingolipids. Cell Mol Life Sci 2007; 64: 2270-2284.
    CrossrefPubMedGoogle Scholar
  • 73 Schnaar RL. Glycolipid-mediated cell-cell recognition in inflammation and nerve regeneration. Arch Biochem Biophys 2004; 426: 163-172.
    CrossrefPubMedGoogle Scholar
  • 74 Stults CL. et al. Glycosphingolipids: structure, biological source, and properties. Methods Enzymol 1989; 179: 167-214.
    PubMedGoogle Scholar
  • 75 Müthing J. Mammalian glycosphingolipids. In: Glycoscience: Chemistry and Chemical Biology. Vol 3. Heidelberg, Germany: Springer-Verlag; 2001: 2220-2249.
    Google Scholar
  • 76 Fantini J. et al. Glycosphingolipid (GSL) microdomains as attachment platforms for host pathogens and their toxins on intestinal epithelial cells: activation of signal transduction pathways and perturbations of intestinal absorption and secretion. Glycoconj J 2000; 17: 173-179.
    CrossrefPubMedGoogle Scholar
  • 77 Hakomori SI. Cell adhesion/recognition and signal transduction through glycosphingolipid microdomain. Glycoconj J 2000; 17: 143-151.
    CrossrefPubMedGoogle Scholar
  • 78 Sonnino S. et al. Dynamic and structural properties of sphingolipids as driving forces for the formation of membrane domains. Chem Rev 2006; 106: 2111-2125.
    CrossrefPubMedGoogle Scholar
  • 79 Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 2000; 1: 31-41.
    CrossrefPubMedGoogle Scholar
  • 80 Schnaar RL. Glycosphingolipids in cell surface recognition. Glycobiology 1991; 1: 477-485.
    CrossrefPubMedGoogle Scholar
  • 81 Feizi T. Carbohydrate-mediated recognition systems in innate immunity. Immunol Rev 2000; 173: 79-88.
    CrossrefPubMedGoogle Scholar
  • 82 Russel RJ. et al. Avian and human receptor binding by hemagglutinins of influenza A viruses. Glycoconj J 2006; 23: 85-92.
    CrossrefPubMedGoogle Scholar
  • 83 Hidari KIPJ. et al. Binding kinetics of influenza viruses to sialic acid-containing carbohydrates. Glycoconj J 2007; 24: 583-590.
    CrossrefPubMedGoogle Scholar
  • 84 Karlsson KA. Animal glycosphingolipids as membrane attachment sites for bacteria. Annu Rev Biochem 1989; 58: 309-350.
    CrossrefPubMedGoogle Scholar
  • 85 Teneberg S. et al. Carbohydrate recognition by enterohemorrhagic Escherichia coli: characterization of a novel glycosphingolipid from cat small intestine. Glycobiology 2004; 14: 187-196.
    PubMedGoogle Scholar
  • 86 Miller-Podraza H. et al. Novel binding epitope for Helicobacter pylori found in neolacto carbohydrate chains: structure and cross-binding properties. J Biol Chem 2005; 280: 19695-19703.
    CrossrefPubMedGoogle Scholar
  • 87 Usuki S. et al. Chemical validation of molecular mimicry: interaction of cholera toxin with Campylobacter lipooligosaccharides. Glycoconj J 2007; 24: 167-180.
    CrossrefPubMedGoogle Scholar
  • 88 Merrit EA, Hol WG. AB5 toxins. Curr Opin Struct Biol 1995; 5: 165-171.
    CrossrefPubMedGoogle Scholar
  • 89 Yowler BC, Schengrund CL. Glycosphingolipids – sweets for botulinum neurotoxin. Glycoconj J 2004; 21: 287-293.
    CrossrefPubMedGoogle Scholar
  • 90 Smith DC. et al. Glycosphingolipids as toxin receptors. Semin Cell Dev Biol 2004; 15: 397-408.
    CrossrefPubMedGoogle Scholar
  • 91 Lingwood CA. et al. Glycolipid binding of purified and recombinant Escherichia coli produced verotoxin in vitro . J Biol Chem 1987; 262: 8834-8839.
    PubMedGoogle Scholar
  • 92 Waddell T. et al. Globotriosyl ceramide is specifically recognized by the Escherichia coli Verocytotoxin 2. Biochem Biophys Res Commun 1988; 152: 674-679.
    CrossrefPubMedGoogle Scholar
  • 93 Waddell T. et al. Induction of verotoxin sensitivity in receptor-deficient cell lines using the receptor glycolipid globotriaosylceramide. Proc Natl Acad Sci USA 1990; 87: 7898-7901.
    CrossrefPubMedGoogle Scholar
  • 94 Head SC. et al. Preparation of VT1 and VT2 hybrid toxins from their purified dissociated subunits. Evidence for B subunit modulation of a subunit function. J Biol Chem 1991; 226: 3617-3621.
    PubMedGoogle Scholar
  • 95 Nakajima H. et al. Kinetic analysis of binding between Shiga toxin and receptor glycolipid Gb3Cer by surface plasmon resonance. J Biol Chem 2001; 276: 42915-42922.
    CrossrefPubMedGoogle Scholar
  • 96 Louise CB, Obrig TG. Specific interaction of Escherichia coli O157:H7-derived Shiga-like toxin II with human renal endothelial cells. J Infect Dis 1995; 172: 1397-1401.
    CrossrefPubMedGoogle Scholar
  • 97 Boyd B. et al. Lipid modulation of glycolipid receptor function. Eur J Biochem 1994; 223: 873-878.
    CrossrefPubMedGoogle Scholar
  • 98 Binnington B. et al. Effect of globotriaosylceramide fatty acid α-hydroxylation on the binding by verotoxin 1 and verotoxin 2. Neurochem Res 2002; 27: 807-813.
    CrossrefPubMedGoogle Scholar
  • 99 Kiarash A. et al. Glycosphingolipid receptor function is modified by fatty acid content. J Biol Chem 1994; 269: 11138-1146.
    PubMedGoogle Scholar
  • 100 Lingwood CA. Aglycone modulation of glycolipid receptor function. Glycoconj J 1996; 13: 495-503.
    CrossrefPubMedGoogle Scholar
  • 101 Sandvig K. et al. Importance of glycolipid synthesis for butyric acid-induced sensitization to Shiga toxin and intracellular sorting of toxin in A431 cells. Mol Biol Cell 1996; 7: 1391-1404.
    CrossrefPubMedGoogle Scholar
  • 102 DeGrandis S. et al. Globotetraosylceramide is recognized by the pig edema disease toxin. J Biol Chem 1989; 264: 12520-12525.
    PubMedGoogle Scholar
  • 103 Samuel JE. et al. Comparison of the glycolipid receptor specificities of Shiga-like toxin type II and Shiga-like toxin type II variants. Infect Immun 1990; 58: 611-618.
    PubMedGoogle Scholar
  • 104 Waddell TE. et al. Interaction of verotoxin 2e with pig intestine. Infect Immun 1996; 64: 1714-1719.
    PubMedGoogle Scholar
  • 105 Tyrrell GJ. et al. Alteration of the carbohydrate binding specificity of verotoxins from Galα1–4Gal to GalNAcβ1–3Galα1–4Gal and vice versa by site-directed mutagenesis of the binding subunit. Proc Natl Acad Sci USA 1992; 89: 524-528.
    CrossrefPubMedGoogle Scholar
  • 106 Boyd B. et al. Alteration of the glycolipid binding specificity of the pig edema toxin from globotetraosyl to globotriaosyl ceramide alters in vivo tissue targetting and results in a verotoxin 1-like disease in pigs. J Exp Med 1993; 177: 1745-1753.
    CrossrefPubMedGoogle Scholar
  • 107 Boyd B, Lingwood C. Verotoxin receptor glycolipid in human renal tissue. Nephron 1989; 51: 207-210.
    CrossrefPubMedGoogle Scholar
  • 108 Jacewicz M. et al. Responses of human intestinal microvascular endothelial cells to Shiga toxins 1 and 2 and pathogenesis of hemorrhagic colitis. Infect Immun 1999; 67: 1439-1444.
    PubMedGoogle Scholar
  • 109 Ren J. et al. Localization of verotoxin receptors in nervous system. Brain Res 1999; 825: 183-188.
    CrossrefPubMedGoogle Scholar
  • 110 Obrig TO. et al. Direct cytotoxic action of Shiga toxin on human vascular endothelial cells. Infect Immun 1988; 56: 2373-2378.
    PubMedGoogle Scholar
  • 111 van Setten PA. et al. Effects of TNFα on verocytotoxin cytotoxicity in purified human glomerular micro-vascular endothelial cells. Kidney Int 1997; 51: 1245-1256.
    CrossrefPubMedGoogle Scholar
  • 112 Pudymaitis A, Lingwood CA. Susceptibility to verotoxin as a function of the cell cycle. J Cell Physiol 1992; 150: 632-639.
    CrossrefPubMedGoogle Scholar
  • 113 Majoul I. et al. Differential expression of receptors for Shiga and Cholera toxin is regulated by the cell cycle. J Cell Sci 2002; 115: 817-826.
    PubMedGoogle Scholar
  • 114 Obrig TG. et al. Endothelial heterogeneity in Shiga toxin receptors and responses. J Biol Chem 1993; 268: 15484-15488.
    PubMedGoogle Scholar
  • 115 Gillard BK. et al. Association of glycosphingolipids with intermediate filaments of human umbilical vein endothelial cells. Exp Cell Res 1991; 192: 433-444.
    CrossrefPubMedGoogle Scholar
  • 116 Gillard BK. et al. Variable subcellular localization of glycosphingolipids. Glycobiology 1993; 3: 57-67.
    CrossrefPubMedGoogle Scholar
  • 117 Gillard BK. et al. Glycosphingolipids of human umbilical vein endothelial cells and smooth muscle cells. Arch Biochem Biophys 1987; 256: 435-445.
    CrossrefPubMedGoogle Scholar
  • 118 Müthing J. et al. Isolation and structural characterization of glycosphingolipids of in vitro propagated human umbilical vein endothelial cells. Glycobiology 1999; 9: 459-468.
    CrossrefPubMedGoogle Scholar
  • 119 Duvar S. et al. Isolation and structural characterization of glycosphingolipids of in vitro propagated bovine aortic endothelial cells. Glycobiology 1997; 7: 1099-1109.
    CrossrefPubMedGoogle Scholar
  • 120 Ohmi K. et al. Human microvascular endothelial cells are strongly sensitive to Shiga toxins. Biochem Biophys Res Commun 1998; 251: 137-141.
    CrossrefPubMedGoogle Scholar
  • 121 Kaye SA. et al. Shiga toxin-associated hemolytic uremic syndrome: interleukin-1β enhancement of Shiga toxin cytotoxicity toward human vascular endothelial cells in vitro . Infect Immun 1993; 61: 3886-91.
    PubMedGoogle Scholar
  • 122 Kanda T. et al. Glycosphingolipid composition of primary cultured human brain microvascular endothelial cells. J Neurosci Res 2004; 78: 141-150.
    CrossrefPubMedGoogle Scholar
  • 123 Duvar S. et al. Glycosphingolipid composition of a new immortalized human cerebromicrovascular endothelial cell line. J Neurochem 2000; 75: 1970-1976.
    PubMedGoogle Scholar
  • 124 van de Kar NCAJ. et al. 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
  • 125 van de Kar NCAJ. et al. Tumor necrosis factor α induces endothelial galactosyltransferase activity and verocytotoxin receptors. Role of specific tumor necrosis factor receptors and protein kinase C. Blood 1995; 85: 734-743.
    PubMedGoogle Scholar
  • 126 Ramegowda B. et al. Interaction of Shiga toxins with human brain microvascular endothelial cells: cytokines as sensitizing agents. J Infect Dis 1999; 180: 1205-1213.
    CrossrefPubMedGoogle Scholar
  • 127 Eisenhauer PB. et al. Tumor necrosis factor alpha increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin. Infect Immun 2001; 69: 1889-1894.
    CrossrefPubMedGoogle Scholar
  • 128 Stricklett PK. et al. Molecular basis for up-regulation by inflammatory cytokines of Shiga toxin 1 cytotoxicity and globotriaosylceramide expression. J Infect Dis 2002; 186: 976-982.
    CrossrefPubMedGoogle Scholar
  • 129 Ergonul Z. et al. Induction of apoptosis of human brain microvascular endothelial cells by Shiga toxin 1. J Infect Dis 2003; 187: 154-158.
    CrossrefPubMedGoogle Scholar
  • 130 O’Loughlin EV, Robins-Browne RM. Effect of Shiga-like toxins on eukaryotic cells. Microbes Infect 2001; 3: 493-507.
    CrossrefPubMedGoogle Scholar
  • 131 Müthing J. High-resolution thin-layer chromatography of gangliosides. J Chromatogr A 1996; 720: 3-25.
    CrossrefPubMedGoogle Scholar
  • 132 Müthing J. TLC in Structure and Recognition Studies of Glycosphingolipids. In: Glycoanalysis Protocols, Methods Mol Biol. Vol. 76 Humana Press Inc.; Totowa, NJ: 1998: 183-195.
    Google Scholar
  • 133 Müthing J. TLC and HPLC of Glycosphingolipids. In: Carbohydrate Analysis by Modern Chromatography and Electrophoresis. J Chrom Libr. Vol. 66 Elsevier Science; 2002: 423-482.
    Google Scholar
  • 134 Müthing J, Heitmann D. Nondestructive detection of gangliosides with lipophilic fluorochromes and their employment for preparative high-performance thin-layer chromatography. Anal Biochem 1993; 208: 121-124.
    CrossrefPubMedGoogle Scholar
  • 135 Müthing J, Kemminer SE. Nondestructive detection of neutral glycosphingolipids with lipophilic anionic fluorochromes and their employment for preparative high-performance thin-layer chromatography. Anal Biochem 1996; 238: 195-202.
    CrossrefPubMedGoogle Scholar
  • 136 Meisen I. et al. Discrimination of neolacto-series gangliosides with α2–3– and α2–6-linked N-acetylneuraminic acid by nanoelectrospray ionization low-energy collision-induced dissociation tandem quadrupole TOF MS. Anal Chem 2003; 75: 5719-5725.
    CrossrefPubMedGoogle Scholar
  • 137 Edgell C-JS. et al. Permanent cell line expressing human factor VIII-related antigen established by hybridization. Proc Natl Acad Sci USA 1983; 80: 3734-3737.
    CrossrefPubMedGoogle Scholar
  • 138 Stins MF. et al. Selective expression of adhesion molecules on human brain microvascular endothelial cells. J Neuroimmunol 1997; 76: 81-90.
    CrossrefPubMedGoogle Scholar
  • 139 Schweppe CH. et al. Glycosphingolipids in vascular endothelial cells: relationship of heterogeneity in Gb3Cer/CD77 receptor expression with differential Shiga toxin 1 cytotoxicity. Glycoconj J 2008; 25: 291-304.
    CrossrefPubMedGoogle Scholar
  • 140 Levery SB. Glycosphingolipid structural analysis and glycosphingolipidomics. Methods Enzymol 2005; 405: 300-369.
    PubMedGoogle Scholar
  • 141 Harvey DJ. Analysis of carbohydrates and glycoconjugates by matrix-assisted laser desorption/ionization mass spectrometry: An update covering the period 1999–2000. Mass Spectrom Rev 2006; 25: 595-662.
    CrossrefPubMedGoogle Scholar
  • 142 Meisen I. et al. Direct analysis of silica gel extracts from immunostained glycosphingolipids by nanoelectrospray ionization quadrupole time-of-flight mass spectrometry. Anal Chem 2004; 76: 2248-2255.
    CrossrefPubMedGoogle Scholar
  • 143 Meisen I. et al. Application of combined high-performance thin-layer chromatography immunostaining and nanoelectrospray ionisation quadrupole time-of-flight tandem mass spectrometry to the structural characterization of high- and low-affinity binding ligands of Shiga toxin 1. Rapid Commun Mass Spectrom 2005; 19: 3659-3665.
    CrossrefPubMedGoogle Scholar
  • 144 Müthing J. Analyses of glycosphingolipids by high-performance liquid chromatography. Methods Enzymol 2000; 312: 45-64.
    PubMedGoogle Scholar
  • 145 Sandvig K. et al. Retrograde transport from the Golgi complex to the ER of both Shiga toxin and the nontoxic Shiga B-fragment is regulated by butyric acid and cAMP. J Cell Biol 1994; 126: 53-64.
    CrossrefPubMedGoogle Scholar
  • 146 Sekino T. et al. Characterization of a Shiga-toxin 1-resistant stock of vero cells. Microbiol Immunol 2004; 48: 377-387.
    CrossrefPubMedGoogle Scholar
  • 147 Dreisewerd K. et al. Analysis of gangliosides directly from thin-layer chromatography plates by infrared matrix-assisted laser desorption/ionization orthogonal time-of-flight mass spectrometry with a glycerol matrix. Anal Chem 2005; 77: 4098-4107.
    CrossrefPubMedGoogle Scholar
  • 148 Distler U. et al. Matching IR-MALDI-o-TOF mass spectrometry with the TLC overlay binding assay and its clinical application for tracing tumor-associated glycosphingolipids in hepatocellular and pancreatic cancer. Anal Chem 2008; 80: 1835-1846.
    CrossrefPubMedGoogle Scholar
  • 149 Lingwood CA. Verotoxin-binding in human renal sections. Nephron 1994; 66: 21-28.
    CrossrefPubMedGoogle Scholar
  • 150 Simons K, Ikonen E. Functional rafts in cell membranes. Nature 1997; 387: 569-572.
    CrossrefPubMedGoogle Scholar
  • 151 Brown DA, London E. Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem 2000; 275: 17221-17224.
    CrossrefPubMedGoogle Scholar
  • 152 Anderson RGW, Jacobson K. A role for lipid shells in targeting proteins to caveolae, rafts, and other lipid domains. Science 2002; 296: 1821-1825.
    CrossrefPubMedGoogle Scholar
  • 153 Kasahara K, Sanai Y. Functional roles of glycosphingolipids in signal transduction via lipid rafts. Glycoconj J 2000; 17: 153-162.
    CrossrefPubMedGoogle Scholar
  • 154 Hoessli DC. et al. Signaling through sphingolipid microdomains of the plasma membrane: The concept of signaling platform. Glycoconj J 2000; 17: 191-197.
    CrossrefPubMedGoogle Scholar
  • 155 Cohen AW. et al. Role of caveolae and caveolins in health and disease. Physiol Rev 2004; 84: 1341-1379.
    CrossrefPubMedGoogle Scholar
  • 156 Hommelgaard AM. et al. Caveolae: stable membrane domains with a potential for internalization. Traffic 2005; 6: 720-724.
    CrossrefPubMedGoogle Scholar
  • 157 Stan RV. Structure and function of endothelial caveolae. Microsc Res Tech 2002; 57: 350-364.
    CrossrefPubMedGoogle Scholar
  • 158 Frank PG. et al. Caveolin, caveolae, and endothelial cell function. Arterioscler Thromb Vasc Biol 2003; 23: 1161-1168.
    CrossrefPubMedGoogle Scholar
  • 159 López JA. et al. Receptors, rafts, and microvesicles in thrombosis and inflammation. J Thromb Haemost 2005; 3: 1737-1744.
    CrossrefPubMedGoogle Scholar
  • 160 Nabi IR, Le PU. Caveolae/raft-dependent endocytosis. J Cell Biol 2003; 161: 673-677.
    CrossrefPubMedGoogle Scholar
  • 161 Parton RG, Richards AA. Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms. Traffic 2003; 4: 724-738.
    CrossrefPubMedGoogle Scholar
  • 162 Kovbasnjuk O. et al. Role of lipid rafts in Shiga toxin 1 interaction with the apical surface of Caco-2 cells. J Cell Sci 2001; 114: 4025-4031.
    PubMedGoogle Scholar
  • 163 Falguières T. et al. Targeting of Shiga toxin B-subunit to retrograde transport route in association with detergent-resistant membranes. Mol Biol Cell 2001; 12: 2453-2468.
    CrossrefPubMedGoogle Scholar
  • 164 Katagiri YU. et al. 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 1999; 274: 35278-35282.
    CrossrefPubMedGoogle Scholar
  • 165 Takenouchi H. et al. Shiga toxin binding to globotriaosyl ceramide induces intracellular signals that mediate cytoskeleton remodeling in human renal carcinoma-derived cells. J Cell Sci 2004; 117: 3911-3922.
    CrossrefPubMedGoogle Scholar
  • 166 Smith DC. et al. The association of Shiga-like toxin with detergent-resistant membranes is modulated by glucosylceramide and is an essential requirement in the endoplasmic reticulum for a cytotoxic effect. Mol Biol Cell 2006; 17: 1375-1387.
    CrossrefPubMedGoogle Scholar
  • 167 Falguières T. et al. Functionally different pools of Shiga toxin receptor, globotriaosyl ceramide, in HeLa cells. FEBS J 2006; 273: 5205-5218.
    CrossrefPubMedGoogle Scholar
  • 168 Lencer WI, Saslowsky D. Raft trafficking of AB5 subunit bacterial toxins. Biochim Biophys Acta 2005; 1746: 314-321.
    CrossrefPubMedGoogle Scholar
  • 169 Gaus K. et al. Visualizing lipid structure and raft domains in living cells with two-photon microscopy. Proc Natl Acad Sci USA 2003; 100: 15554-15559.
    CrossrefPubMedGoogle Scholar
  • 170 Kemper B. et al. Investigation of living pancreas tumor cells by digital holographic microscopy. J Biomed Opt 2006; 11: 34005.
    CrossrefPubMedGoogle Scholar
  • 171 Müthing J. et al. Mistletoe lectin I is a sialic acid-specific lectin with strict preference to gangliosides and glycoproteins with terminal Neu5Acα2–6Galβ1 –4GlcNAc residues. Biochemistry 2004; 43: 2996-3007.
    CrossrefPubMedGoogle Scholar
  • 172 Gerber A. 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.
    CrossrefPubMedGoogle Scholar
  • 173 Banatvala N. et al. The United States national prospective hemolytic uremic syndrome study: microbiologic, serologic, clinical, and epidemiologic findings. J Infect Dis 2001; 183: 1063-1070.
    CrossrefPubMedGoogle Scholar
  • 174 Tozzi AE. et al. Shiga toxin-producing Escherichia coli infections associated with hemolytic uremic syndrome, Italy, 1988–2000. Emerg Infect Dis 2003; 9: 106-108.
    CrossrefPubMedGoogle Scholar