Facing glycosphingolipid–Shiga toxin interaction: dire straits for endothelial cells of the human vasculature
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- 作者：Andreas Bauwens (1)
Josefine Betz (1)
Iris Meisen (1) (2)
Bj?rn Kemper (3)
Helge Karch (1)
Johannes Müthing (1) (2) - 关键词：Gb3Cer ; Gb4Cer ; Glycolipids ; HUS ; Lipid rafts ; Mass spectrometry ; Membrane microdomains
- 刊名：Cellular and Molecular Life Sciences (CMLS)
- 出版年：2013
- 出版时间：February 2013
- 年：2013
- 卷：70
- 期：3
- 页码：425-457
- 全文大小：1404KB
- 参考文献：1. Sahni SK (2007) Endothelial cell infection and hemostasis. Thromb Res 119:531-49
2. Chi JT, Chang HY, Haraldsen G, Jahnsen FL, Troyanskaya OG, Chang DS, Wang Z, Rockson SG, van de Rijn M, Botstein D, Brown PO (2003) Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci USA 100:10623-0628
3. Pober JS, Min W, Bradley JR (2009) Mechanisms of endothelial dysfunction, injury, and death. Annu Rev Pathol 4:71-5
4. Schnittler H, Preissner KT (2009) Between microbial attack and defence: the endothelium as a vulnerable player in infectious diseases. Thromb Haemost 102:1011-013
5. Lemichez E, Lecuit M, Nassif X, Bourdoulous S (2010) Breaking the wall: targeting of the endothelium by pathogenic bacteria. Nat Rev Microbiol 8:93-04
6. Opitz B, Hippenstiel S, Eitel J, Suttorp N (2007) Extra- and intracellular innate immune recognition in endothelial cells. Thromb Haemost 98:319-26
7. Cardoso FL, Brites B, Brito MA (2010) Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev 64:328-63
8. Ballermann BJ (2007) Contribution of the endothelium to the glomerular permselectivity barrier in health and disease. Nephron Physiol 106:19-5
9. Satchell SC, Braet F (2009) Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am J Physiol Renal Physiol 296:F947–F956
10. Chiang CK, Inagi R (2010) Glomerular diseases: genetic causes and future therapeutics. Nat Rev Nephrol 6:539-54
11. Patrakka J, Tryggvason K (2010) Molecular make-up of the glomerular filtration barrier. Biochem Biophys Res Commun 396:164-69
12. Pate M, Damarla V, Chi DS, Negi S, Krishnaswamy G (2010) Endothelial cell biology: role in the inflammatory response. Adv Clin Chem 52:109-30
13. Harding M, Kubes P (2012) Innate immunity in the vasculature: interactions with pathogenic bacteria. Curr Opin Microbiol 15:85-1
14. Vestweber D (2007) Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. Immunol Rev 218:178-96
15. Tesfamariam B, DeFelice AF (2007) Endothelial injury in the initiation and progression of vascular disorders. Vasc Pharmacol 46:229-37
16. Nataro JP, Kaper JB (1998) Diarrheagenic / Escherichia coli. Clin Microbiol Rev 11:142-01
17. Johnson TJ, Nolan LK (2009) Pathogenomics of virulence plasmids of / Escherichia coli. Microbiol Mol Biol Rev 73:750-74
18. Farfan MJ, Torres AG (2012) Molecular mechanisms that mediate colonization of Shiga toxin-producing / Escherichia coli strains. Infect Immun 80:903-13
19. Melton-Celsa A, Mohawk K, Teel L, O’Brien A (2012) Pathogenesis of Shiga-toxin producing / Escherichia coli. Curr Top Microbiol Immunol 357:67-03
20. Schmidt MA (2010) LEEways: tales of EPEC, ATEC and EHEC. Cell Microbiol 12:1544-552
21. Lingwood CA (1996) Role of verotoxin receptors in pathogenesis. Trends Microbiol 4:147-53
22. Karch H, Tarr PI, Bielaszewska M (2005) Enterohaemorrhagic / Escherichia coli in human medicine. Int J Med Microbiol 295:405-18
23. Karch H, Friedrich AW, Gerber A, Zimmerhackl LB, Schmidt MA, Bielaszewska M (2006) New aspects in the pathogenesis of enteropathic hemolytic uremic syndrome. Semin Thromb Hemost 32:105-12
24. Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing / Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073-086
25. Zoja C, Buelli S, Morigi M (2010) Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction. Pediatr Nephrol 25:2231-240
26. Friedrich AW, Zhang W, Bielaszewska M, Mellmann A, K?ck R, Fruth A, Tsch?pe H, Karch H (2007) Prevalence, virulence profiles, and clinical significance of Shiga toxin-negative variants of enterohemorrhagic / Escherichia coli O157 infection in humans. Clin Infect Dis 45:39-5
27. Mellmann A, Bielaszewska M, Karch H (2009) Intrahost genome alterations in enterohemorrhagic / Escherichia coli. Gastroenterology 136:1925-938
28. Tsai HM (2006) The molecular biology of thrombotic microangipathy. Kidney Int 70:16-3
29. Karpman D, Sartz L, Johnson S (2010) Pathophysiology of typical hemolytic uremic syndrome. Semin Thromb Hemost 36:575-85
30. Obata F (2010) Influence of / Escherichia coli Shiga toxin on the mammalian central nervous system. Adv Appl Microbiol 71:1-9
31. Karmali MA, Gannon V, Sargeant JM (2010) Verocytotoxin-producing / Escherichia coli (VTEC). Vet Microbiol 140:360-70
32. Ferens WA, Hovde CJ (2011) / Escherichia coli O157:H7: animal reservoir and sources of human infection. Foodborne Pathog Dis 8:465-87
33. Hoey DEE, Currie C, Else RW, Nutikka A, Lingwood CA, Gally DL, Smith DGE (2002) Expression of receptors for verotoxin 1 from / Escherichia coli O157 on bovine intestinal epithelium. J Med Microbiol 51:143-49
34. Pennington H (2010) / Escherichia coli O157. Lancet 376:1428-435
35. Wong CS, Mooney JC, Brandt JR, Staples AO, Jelacic S, Boster DR, Watkins SL, Tarr PI (2012) Risk factors for the hemolytic uremic syndrome in children infected with / Escherichia coli O157:H7: a multivariable analysis. Clin Infect Dis 55:33-1
36. Hunt JM (2010) Shiga toxin-producing / Escherichia coli (STEC). Clin Lab Med 30:21-5
37. Mellmann A, Bielaszewska M, K?ck R, Friedrich AW, Fruth A, Middendorf B, Harmsen D, Schmidt MA, Karch H (2008) Analysis of collection of hemolytic uremic syndrome-associated enterohemorrhagic / Escherichia coli. Emerg Infect Dis 14:1287-290
38. Zimmerhackl LB, Rosales A, Hofer J, Riedl M, Jungraithmayr T, Mellmann A, Bielaszewska M, Karch H (2010) Enterohemorrhagic / Escherichia coli O26:H11-associated hemolytic uremic syndrome: bacteriology and clinical presentation. Semin Thromb Hemost 36:586-93
39. Jenke C, Lindstedt BA, Harmsen D, Karch H, Brandal LT, Mellmann A (2011) Comparison of multilocus variable-number tandem-repeat analysis and multilocus sequence typing for differentiation of hemolytic-uremic syndrome-associated / Escherichia coli (HUSEC) collection strains. J Clin Microbiol 49:3644-646
40. Kunzendorf U, Karch H, Werber D, Haller H (2011) Recent outbreak of hemolytic uremic syndrome in Germany. Kidney Int 80:900-02
41. 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, Müller L, King LA, Rosner B, Buchholz U, Stark K, Krause G, HUS Investigation Team (2011) Epidemic profile of Shiga-toxin-producing / Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 365:1771-780
42. Frank C, Faber MS, Askar M, Bernard H, Fruth A, Gilsdorf A, H?hle M, Karch H, Krause G, Prager R, Spode A, Stark K, Werber D (2011) Large and ongoing outbreak of haemolytic uraemic syndrome, Germany, May 2011. Euro Surveill 16(21). pii:19878
43. Bielaszewska M, Mellmann A, Zhang W, K?ck R, Fruth A, Bauwens A, Peters G, Karch H (2011) Characterisation of the / Escherichia coli strain associated with an outbreak of haemolytic uraemic syndrome in Germany, 2011: a microbiological study. Lancet Infect Dis 11:671-76
44. Mellmann A, Harmsen D, Cummings CA, Zentz EB, Leopold SR, Rico A, Prior K, Szczepanowski R, Ji Y, Zhang W, McLaughlin SF, Henkhaus JK, Leopold B, Bielaszweska M, Prager R, Brzoska PM, Moore RL, Guenther S, Rothberg JM, Karch J (2011) Prospective genomic characterization of the German enterohemorrhagic / Escherichia coli O104:H4 outbreak by rapid next generation sequencing technology. PLoS One 6(7):e22751
45. Lo? JM, Lo? M, W?grzyn G (2011) Bacteriophages carrying Shiga toxin genes: genomic variations, detection and potential treatment of pathogenic bacteria. Future Microbiol 6:909-24
46. Mauro SA, Koudelka GB (2011) Shiga toxin: expression, distribution, and its role in the environment. Toxins 3:608-25
47. Richardson SE, Karmali MA, Becker LE, Smith CR (1988) The histopathology of the hemolytic uremic syndrome associated with verocytotoxin-producing / Escherichia coli infections. Hum Pathol 19:1102-108
48. Ruggenenti P, Noris M, Remuzzi G (2001) Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60:831-46
49. Bielaszewska M, Karch H (2005) Consequences of enterohaemorrhagic / Escherichia coli infection for the vascular endothelium. Thromb Haemost 94:312-18
50. Sandvig K (2001) Shiga toxins. Toxicon 39:1629-635
51. Müthing J, Schweppe CH, Karch H, Friedrich AW (2009) Shiga toxins, glycosphingolipid diversity, and endothelial cell injury. Thromb Haemost 101:252-64
52. Ling H, Boodhoo A, Hazes B, Cummings MD, Armstrong GD (1998) Structure of the Shiga-like toxin I B-pentamer complexed with an analogue of its receptor Gb3. Biochemistry 37:1777-788
53. Jackson MP, Neill RJ, O’Brien AD, Holmes RK, Newland JW (1987) 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 44:109-14
54. 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 262:8834-839
55. 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 152:674-79
56. Müthing J, Meisen I, Zhang W, Bielaszewska M, Mormann M, Bauerfeind R, Schmidt MA, Friedrich AW, Karch H (2012) Promiscuous Shiga toxin 2e and its intimate relationship to Forssman. Glycobiology 22:849-62
57. 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 266:3617-621
58. Fraser ME, Cherney MM, Marcato P, Mulvey GL, Armstrong GD, James MNG (2006) Binding of adenine to Stx2, the protein toxin from / Escherichia coli O157:H7. Acta Crystallogr Sect F Struct Biol Cryst Commun 62:627-30
59. Obrig TG (2010) / Escherichia coli Shiga toxin mechanisms of action in renal disease. Toxins 2:2769-794
60. 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 160:994-98
61. 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 185:74-4
62. Orth D, Würzner R (2010) Complement in typical hemolytic uremic syndrome. Semin Thromb Hemost 36:620-24
63. Schüller S (2011) Shiga toxin interaction with human intestinal epithelium. Toxins 3:626-39
64. Te Loo DMWM, Monnens LAH, van der Velden TJAM, Vermeer MA, Preyers F, Demacker PNM, van den Heuvel LPWJ, van Hinsbergh VWM (2000) Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome. Blood 95:3396-402
65. Brigotti M, Carnicelli D, Ravanelli E, Barbieri S, Ricci F, Bontadini A, Tozzi AE, Scavia G, Caprioli A, Tazzari PL (2008) Interactions between Shiga toxins and human polymorphonuclear leukocytes. J Leukoc Biol 84:1019-027
66. Arfilli V, Carnicelli D, Rocchi L, Ricci F, Pagliaro P, Tazzari PL, Brigotti M (2010) Shiga toxin 1 and ricin A chain bind to human polymorphonuclear leucocytes through a common receptor. Biochem J 432:173-80
67. Brigotti M, Tazzari PL, Ravanelli E, Carnicelli D, Barbieri S, Rocchi L, Arfilli V, Scavia G, Ricci F, Bontadini A, Alfieri RR, Pretonini PG, Pecoraro C, Tozzi AE, Caprioli A (2010) Endothelial damage induced by Shiga toxins delivered by neutrophils during transmigration. J Leukoc Biol 88:201-10
68. Brigotti M, Tazzari PL, Ravanelli E, Carnicelli D, Rocchi L, Arfilli V, Scavia G, Minelli F, Ricci F, Pagliaro P, Ferretti AV, Pecoraro C, Paglialonga F, Edefonti A, Procaccino MA, Tozzi AE, Caprioli A (2011) Clinical relevance of Shiga toxin concentrations in the blood of patients with hemolytic uremic syndrome. Pediatr Infect Dis 30:486-90
69. Brigotti M, Carnicelli D, Arfilli V, Rocchi L, Ricci F, Pagliaro P, Tazzari PL, Vara AG, Amelia M, Manoli F, Monti S (2011) Change in conformation with reduction of α-helix content causes loss of neutrophil binding activity in fully cytotoxic Shiga toxin 1. J Biol Chem 286:34514-4521
70. Ramegowda B, Tesh VL (1996) Differentiation-associated toxin receptor modulation, cytokine production, and sensitivity of Shiga-like toxins in human monocytes and monocytic cell lines. Infect Immun 64:1173-180
71. Geelen JM, van der Velden TJ, van den Heuvel LP, Monnens LA (2007) Interactions of Shiga-like toxin with human peripheral blood monocytes. Pediatr Nephrol 22:1181-187
72. Lee SY, Lee MS, Cherla RP, Tesh VL (2008) Shiga toxin 1 induces apoptosis through the endoplasmic reticulum stress response in human monocytic cells. Cell Microbiol 10:770-80
73. 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 358:510-12
74. Johannes L, Goud B (2000) Facing inward from compartment shores: how many pathways were we looking for? Traffic 1:119-23
75. Sandvig K, van Deurs B (2002) Transport of protein toxins into cells: pathways used by ricin, cholera toxin and Shiga toxin. FEBS Lett 529:49-3
76. Spooner RA, Smith DC, Easton AJ, Roberts LM, Lord JM (2006) Retrograde transport pathways utilised by viruses and protein toxins. Virol J 3:26
77. R?mer W, Berland L, Chambon V, Gaus K, Windschiegl B, Tenza D, Aly MRE, 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 450:670-75
78. Johannes L, R?mer W (2010) Shiga toxins—from cell biology to biomedical applications. Nat Rev Microbiol 8:105-16
79. Sandvig K, Torgersen ML, Engedal N, Skotland T, Iversen TG (2010) Protein toxins from plants and bacteria: probes for intracellular transport and tools in medicine. FEBS Lett 584:2626-634
80. Sandvig K, Bergan J, Dyve AB, Skotland T, Torgersen ML (2010) Endocytosis and retrograde transport of Shiga toxin. Toxicon 56:1181-185
81. Ewers H, Helenius A (2011) Lipid-mediated endocytosis. Cold Spring Harb Perspect Biol 3:a004721
82. Yu M, Haslam DB (2005) Shiga toxin is transported from the endoplasmic reticulum following interaction with the luminal chaperone HEDJ/ERdj3. Infect Immun 73:2524-532
83. Garred O, Dubinina E, Holm PK, Olsnes S, van Deurs B, Kozlov JV, Sandvig K (1995) Role of processing and intracellular transport for optimal toxicity of Shiga toxin and toxin mutants. Exp Cell Res 218:39-9
84. Endo Y, Tsurugi K, Yutsudo T, Takeda Y, Ogasawara T, Igarashi K (1988) Site of action of a Vero toxin (VT2) from / Escherichia coli O157:H7 and of Shiga toxin on eukaryotic ribosomes. RNA / N-glycosidase activity of the toxins. Eur J Biochem 171:45-0
85. O’Brien AD, Tesh VL, Donohue-Rolfe A, Jackson MP, Olsnes S, Sandvig K, Lindberg AA, Keusch GT (1992) Shiga toxin: biochemistry, genetics, mode of action, and role in pathogenesis. Curr Top Microbiol Immunol 180:65-4
86. Barbieri L, Valbonesi P, Brigotti M, Montanara L, Stirpe F, Sperti S (1998) Shiga-like toxin I is a polynucleotide:adenosine glycosidase. Mol Microbiol 29:661-62
87. McCluskey AJ, Bolewska-Pedyczak E, Jarvik N, Chen G, Sidhu SS, Gariépy 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(2):e31191
88. Tesh VL (2012) Activation of cell stress response pathways by Shiga toxins. Cell Microbiol 14:1-
89. Brigotti M, Accorsi P, Carnicelli D, Rizzi S, González Vara A, Montanaro L, Sperti S (2001) Shiga toxin 1: damage to DNA in vitro. Toxicon 39:341-48
90. Brigotti M, Carnicelli D, Vara AG (2004) Shiga toxin 1 acting on DNA in vitro is a heat-stable enzyme not requiring proteolytic activation. Biochimie 86:305-09
91. Sestili P, Alfieri R, Carnicelli D, Martinelli C, Barbieri L, Stirpe F, Bonelli M, Petronini PG, Brigotti M (2005) Shiga toxin 1 and ricin inhibit the repair of H2O2-induced DNA single strand breaks in cultured mammalian cells. DNA Repair 4:271-77
92. Sandvig K, Torgersen ML, Raa HA, van Deurs B (2008) Clathrin-independent endocytosis: from nonexisting to an extreme degree of complexity. Histochem Cell Biol 129:267-76
93. Obrig TG, del Vecchio PJ, Brown JE, Moran TP, Rowland BM, Judge TK, Rothman SW (1988) Direct cytotoxic action of Shiga toxin on human vascular endothelial cells. Infect Immun 56:2373-378
94. Louise CB, Obrig TG (1991) Shiga toxin-associated hemolytic-uremic syndrome: combined cytotoxic effects of Shiga toxin, Interleukin-1β, and tumor necrosis factor alpha on human vascular endothelial cells in vitro. Infect Immun 59:4173-179
95. Louise CB, Obrig TG (1992) Shiga toxin-associated hemolytic uremic syndrome: combined cytotoxic effects of Shiga toxin and lipopolysaccharide (endotoxin) on human vascular endothelial cells in vitro. Infect Immun 60:1536-543
96. van de Kar NCAJ, Monnens LAH, Karmali MA, van Hinsbergh VWM (1992) 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 80:2755-764
97. Kaye SA, Louise CB, Boyd B, Lingwood CA, Obrig TG (1993) Shiga toxin-associated hemolytic uremic syndrome: interleukin-1β enhancement of Shiga toxin cytotoxicity toward human vascular endothelial cells in vitro. Infect Immun 61:3886-891
98. Obrig TG, Louise CB, Lingwood CA, Boyd B, Barley-Malony L, Daniel TO (1993) Endothelial heterogeneity in Shiga toxin receptors and responses. J Biol Chem 268:15484-5488
99. van de Kar NCAJ, Kooistra T, Vermeer M, Lesslauer W, Monnens LAH, van Hinsbergh VWM (1995) Tumor necrosis factor α induces endothelial galactosyl transferase activity and verocytotoxin receptors. Role of specific tumor necrosis factor receptors and protein kinase C. Blood 85:734-43
100. Louise CB, Tran MC, Obrig TG (1997) Sensitization of human umbilical vein endothelial cells to Shiga toxin: involvement of protein kinase C and NF-κB. Infect Immun 65:3337-344
101. Stone MK, Kolling GL, Lindner MH, Obrig TG (2008) p38 Mitogen-activated protein kinase mediates lipopolysaccharide and tumor necrosis factor alpha induction of Shiga toxin 2 sensitivity in human umbilical vein endothelial cells. Infect Immun 76:1115-121
102. Nolasco LH, Turner NA, Bernardo A, Tao Z, Cleary TG, Dong J, Moake JL (2005) Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impar ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood 106:4199-209
103. Huang J, Motto DG, Bundle DR, Sadler JE (2010) Shiga toxin B subunits induce vWF secretion by human endothelial cells and thrombotic microangiopathy in ADAMST13-deficient mice. Blood 116:3653-659
104. Liu F, Huang J, Sadler JE (2011) Shiga toxin (Stx)1B and Stx2B induce von Willebrand factor secretion from human umbilical vein endothelial cells through different signaling pathways. Blood 118:3392-398
105. Morigi M, Micheletti G, Figliuzzi M, Imberti B, Karmali MA, Remuzzi A, Remuzzi G, Zoja C (1995) Verotoxin-1 promotes leukocyte adhesion to cultured endothelial cells under physiologic flow conditions. Blood 86:4553-558
106. Geelen JM, Valsecchi F, van der Velden T, van den Heuvel L, Monnens L, Morigi M (2008) Shiga-toxin-induced firm adhesion of human leukocytes to endothelium is in part mediated by heparan sulfate. Nephrol Dial Transplant 23:3091-095
107. Zanchi C, Zoja C, Morigi M, Valsecchi F, Liu XY, Rottoli D, Locatelli M, Buelli S, Pezzotta A, Mapelli P, Geelen J, Remuzzi G, Hawiger J (2008) Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. J Immunol 181:1460-469
108. Brigotti M, Alfieri R, Sestili P, Bonelli M, Petronini PG, Guidarelli A, Barbieri L, Stirpe F, Sperti S (2002) Damage to nuclear DNA induced by Shiga toxin 1 and ricin in human endothelial cells. FASEB J 16:365-72
109. Matussek A, Lauber J, Bergau A, Hansen W, Rohde M, Dittmar KEJ, 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 102:1323-332
110. Torgersen ML, Engedal N, Pedersen AMG, Husebye H, Espevik T, Sandvig K (2011) Toll-like receptor facilitates binding of Shiga toxin to colon carcinoma and primary endothelial cells. FEMS Immunol Med Microbiol 61:63-5
111. Goerdt S, Sorg C (1992) Endothelial heterogeneity and the acquired immunodeficiency syndrome: a paradigm for the pathogenesis of vascular disorders. Clin Invest 70:89-8
112. Augustin HG, Kozian DH, Johnson RC (1994) Differentiation of endothelial cells: analysis of the constitutive and activated endothelial cell phenotypes. BioEssays 16:901-06
113. Aird WC (2003) Endothelial cell heterogeneity. Crit Care Med 31:S221–S230
114. Aird WC (2008) Endothelium in health and disease. Pharmacol Rep 60:139-43
115. Ohmi K, Kiyokawa N, Takeda T, Fujimoto J (1998) Human microvascular endothelial cells are strongly sensitive to Shiga toxins. Biochem Biophys Res Commun 251:137-41
116. Morigi M, Galbusera M, Binda E, Imberti B, Gastoldi S, Remuzzi A, Zoja C, Remuzzi G (2001) Verotoxin-1-induced up-regulation of adhesive molecules renders microvascular endothelial cells thrombogenic at high shear stress. Blood 98:1828-835
117. Obrig TG, Seaner RM, Bentz M, Lingwood CA, Boyd B, Smith A, Narrow W (2003) Induction by sphingomyelinase of Shiga toxin receptor and Shiga toxin 2 sensitivity in human microvascular endothelial cells. Infect Immun 71:845-49
118. Jacewicz MS, Acheson DWK, Binion DG, West GA, Lincicome LL, Fiocchi C, Keusch GT (1999) Responses of human intestinal microvascular endothelial cells to Shiga toxins 1 and 2 and pathogenesis of hemorrhagic colitis. Infect Immun 67:1439-444
119. Keusch GT, Acheson DWK, Aaldering L, Erban J, Jacewicz MS (1996) Comparison of the effects of Shiga-like toxin 1 on cytokine- and butyrate-treated human umbilical and saphenous vein endothelial cells. J Infect Dis 173:1164-170
120. Yoshida T, Sugiyama T, Koide N, Mori I, Yokochi T (2003) Human microvascular endothelial cells resist Shiga toxins by IFN-γ treatment in vitro. Microbiology 149:2609-614
121. Louise CB, Obrig TG (1994) Human renal microvascular endothelial cells as a potential target in the development of the hemolytic uremic syndrome as related to fibrinolysis factor expression, in vitro. Microvasc Res 47:377-87
122. 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 172:1397-401
123. van Setten PA, van Hinsbergh VWM, van der Velden TJAN, van de Kar NCAJ, Vermeer M, Mahan JD, Assmann KJM, van den Heuvel LPWJ, Monnens LAH (1997) Effects of TNFα on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells. Kidney Int 51:1245-256
124. Warnier M, R?mer 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 70:2085-091
125. Nestoridi E, Tsukurov O, Kushak RI, Ingelfinger JR, Grabowski EF (2005) Shiga toxin enhances functional tissue factor on human glomerular endothelial cells: implications for the pathophysiology of hemolytic uremic syndrome. J Thromb Haemost 3:752-62
126. Te Loo DM, Monnens L, van der Velden T, Karmali M, van den Heuvel L, van Hinsbergh V (2006) Shiga toxin-1 affects nitric oxide production by human glomerular endothelial and mesangial cells. Pediatr Nephrol 21:1815-823
127. Herrera M, Garvin JL (2005) Recent advances in the regulation of nitric oxide in the kidney. Hypertension 45:1062-067
128. Guessous F, Marcinkiewicz M, Polanowska-Grabowska R, Kongkhum S, Heatherly D, Obrig T, Gear ARL (2005) Shiga toxin 2 and lipopolysaccharide induce human microvascular endothelial cells to release chemokines and factors that stimulate platelet function. Infect Immun 73:8306-316
129. Zoja C, Angioletti S, Donadelli R, Zanchi C, Tomasoni S, Binda E, Imberti B, te Loo M, Monnens L, Remuzzi G, Morigi M (2002) Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via NF-κB dependent up-regulation of IL-8 and MCP-1. Kidney Int 62:846-56
130. Greinacher A, Friesecke S, Abel P, Dressel A, Stracke S, Fiene M, Ernst F, Selleng K, Weissenborn K, Schmidt BM, Schiffer M, Felix SB, Lerch MM, Kielstein JT, Mayerle J (2011) Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with / Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial. Lancet 378:1166-173
131. Matano S, Inamura K, Konishi M, Okumura T, Kawai H, Okamura T, Takat Y, Yamada K, Obata M, Nagata H, Muramoto Y, Sugimoto T (2011) Encephalopathy, disseminated intravascular coagulation, and hemolytic-uremic syndrome after infection with enterohemorrhagic / Escherichia coli O111. J Infect Chemother. doi:10.1007/s10156-011-0336-9
132. Ramegowda B, Samuel JE, Tesh VL (1999) Interaction of Shiga toxins with human brain microvascular endothelial cells. J Infect Dis 180:1205-213
133. Eisenhauer PB, Chaturvedi P, Fine RE, Ritchie AJ, Pober JS, Cleary TG, Newburg DS (2001) Tumor necrosis alpha increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin. Infect Immun 69:1889-894
134. Stricklett PK, Hughes AK, Ergonul Z, Kohan DE (2002) Molecular basis for up-regulation by inflammatory cytokines of Shiga toxin 1 cytotoxicity and globotriaosylceramide expression. J Infect Dis 186:976-82
135. Hughes AK, Ergonul Z, Stricklett PK, Kohan DE (2002) Molecular basis for high renal cell sensitivity to the cytotoxic effects of Shigatoxin-1: upregulation of globotriaosylceramide expression. J Am Soc Nephrol 13:2239-245
136. Eisenhauer PB, Jacewicz MS, Conn KJ, Koul O, Wells JM, Fine RE, Newburg DS (2004) Escherichia coli Shiga toxin 1 and TNF-α induce cytokine release by human cerebral microvascular endothelial cells. Microb Pathog 36:189-96
137. Stricklett PK, Hughes AK, Kohan DE (2005) Inhibition of p38 mitogen-activated protein kinase ameliorates cytokine up-regulated Shigatoxin-1 toxicity in human brain microvascular endothelial cells. J Infect Dis 191:461-71
138. Pijpers AHJM, van Setten PA, van den Heuvel LPWJ, Assmann KJM, Dijkman HBPM, Pennings AHM, Monnens LAH, van Hinsbergh VWM (2001) Verocytotoxin-induced apoptosis of human microvascular endothelial cells. J Am Soc Nephrol 12:767-78
139. Yoshida T, Fukuda M, Koide N, Ikeda H, Sugiyama T, Kato Y, Ishikawa N, Yokochi T (1999) Primary cultures of human endothelial cells are susceptible to low doses of Shiga toxins and undergo apoptosis. J Infect Dis 180:2048-052
140. Molostov G, Morris A, Rose P, Basu S (2001) Interaction of cytokines and growth factor in the regulation of verotoxin-induced apoptosis in cultured human endothelial cells. Br J Haematol 113:891-97
141. Erwert RD, Winn RK, Harlan JM, Bannerman DD (2002) Shiga-like toxin inhibition of FLICE-like inhibitory protein expression sensitizes endothelial cells to bacterial lipopolysaccharide-induced apoptosis. J Biol Chem 277:40567-0574
142. Ergonul Z, Hughes AK, Kohan DE (2003) Induction of apoptosis of human brain microvascular endothelial cells by Shiga toxin 1. J Infect Dis 187:154-58
143. Erwert RD, Eiting KT, Tupper JC, Winn RK, Harlan JM, Bannerman DD (2003) Shiga toxin induces decreased expression of the anti-apoptotic protein Mc1-1 concomitant with the onset of endothelial apoptosis. Microb Pathog 35:87-3
144. Fuji J, Wood K, Matsuda F, Carneiro-Filho BA, Schlegel KH, Yutsudo T, Binnington-Boyd B, Lingwood CA, Obata F, Kim KS, Yoshida SI, Obrig T (2008) Shiga toxin 2 causes apoptosis in human brain microvascular endothelial cells via C/EBP homologous protein. Infect Immun 76:3679-689
145. Tesh VL (2010) Induction of apoptosis by Shiga toxins. Future Microbiol 5:431-53
146. Bauwens A, Bielaszewska M, Kemper B, Langehanenberg P, von Bally G, Reichelt R, Mulac D, Humpf HU, Friedrich AW, Kim KS, Karch H, Müthing J (2011) Differential cytotoxic actions of Shiga toxin 1 and Shiga toxin 2 on microvascular and macrovascular endothelial cells. Thromb Haemost 105:515-28
147. Carl D, Kemper B, Wernicke G, von Bally G (2004) Parameter-optimized digital holographic microscope for high-resolution living-cell analysis. Appl Opt 43:6536-544
148. Marquet P, Rappaz B, Magistretti PJ, Cuche E, Emery Y, Colomb T, Depeursinge C (2005) Digital holographic microscopy: a noninvasive contrast imaging technique allowing quantitative visualization of living cells with subwavelength axial accuracy. Opt Lett 30:468-70
149. Depeursinge C, Colomb T, Emery Y, Kühn J, Charrière F, Rappaz B, Marquet P (2007) Digital holographic microscopy applied to life sciences. Conf Proc IEEE Eng Med Biol Soc 2007:6244-247
150. Langehanenberg P, Ivanova L, Bernhardt I, Ketelhut S, Vollmer A, Dirksen D, Georgiev G, von Bally G, Kemper B (2009) Automated three-dimensional tracking of living cells by digital holographic microscopy. J Biomed Opt 14:014018
151. Kemper B, von Bally G (2008) Digital holographic microscopy for live cell applications and technical inspection. Appl Opt 47:A52–A61
152. Kemper B, Bauwens A, Vollmer A, Ketelhut S, Langehanenberg P, Müthing J, Karch H, von Bally G (2010) Label-free quantitative cell division monitoring of endothelial cells by digital holographic microscopy. J Biomed Opt 15:036009
153. Levery SB (2005) Glycosphingolipid structural analysis and glycosphingolipidomics. Methods Enzymol 405:300-69
154. Merrill AH Jr (2011) Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 111:6387-422
155. Kolter T, Proia RL, Sandhoff K (2002) Combinatorial ganglioside biosynthesis. J Biol Chem 277:25859-5862
156. Sandhoff K, Kolter T (2003) Biosynthesis and degradation of mammalian glycosphingolipids. Philos Trans R Soc Lond B 358:847-61
157. Lahiri S, Futerman AH (2007) The metabolism and function of sphingolipids and glycosphingolipids. Cell Mol Life Sci 64:2270-284
158. Stults CLM, Sweeley CC, Macher BA (1989) Glycosphingolipids: structure, biological source, and properties. Methods Enzymol 179:167-14
159. Lochnit G, Geyer R, Heinz E, Rietschel ET, Z?hringer U, Müthing J (2001) Chemical biology and biomedicine: glycolipids and glycosphingolipids. In: Fraser-Reid B, Tatsuta K, Thiem J (eds) Glycoscience: chemistry and chemical biology, vol III. Springer, Heidelberg, pp 2183-249
160. Chester MA (1999) IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids. Recommendations 1997. Glycoconj J 16:1-
161. Hakomori SI (2008) Structure and function of glycosphingolipids and sphingolipids: recollections and future trends. Biochim Biophys Acta 1780:325-46
162. Lopez PHH, Schnaar R (2009) Gangliosides in cell recognition and membrane protein regulation. Curr Opin Struct Biol 19:549-57
163. Yu RK, Nakatani Y, Yanagisawa M (2009) The role of glycosphingolipid metabolism in the developing brain. J Lipid Res 50:S440–S445
164. Stancevic B, Kolesnick R (2010) Ceramide-rich platforms in transmembrane signaling. FEBS Lett 584:1728-740
165. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139-50
166. Gault CR, Obeid LM, Hannun YA (2010) An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 688:1-3
167. Karlsson KA (1989) Animal glycosphingolipids as membrane attachment sites for bacteria. Annu Rev Biochem 58:309-50
168. Smith DC, Lord JM, Roberts LM, Johannes L (2004) Glycosphingolipids as toxin receptors. Semin Cell Dev Biol 15:397-08
169. Lencer WI (2004) Retrograde transport of cholera toxin into the ER of host cells. Int J Med Microbiol 293:491-94
170. Lencer WI, Saslowsky D (2005) Raft trafficking of AB5 subunit bacterial toxins. Biochim Biophys Acta 1746:314-21
171. Pina DG, Johannes L (2005) Cholera and Shiga toxin B-subunits: thermodynamic and structural considerations for function and biomedical applications. Toxicon 45:389-93
172. Fujinaga Y (2006) Transport of bacterial toxins into target cells: pathways followed by cholera toxin and botulinum progenitor toxin. J Biochem 140:155-60
173. Chinnapen DJF, Chinnapen H, Saslowsky D, Lencer WI (2007) Rafting with cholera toxin: endocytosis and trafficking from plasma membrane to ER. FEMS Microbiol Lett 266:129-37
174. Binz T, Rummel A (2009) Cell entry strategy of clostridial neurotoxin. J Neurochem 109:1584-595
175. Brunger AT, Rummel A (2009) Receptor and substrate interactions of clostridial neurotoxins. Toxicon 54:550-60
176. Kroken AR, Karalewitz AP, Fu Z, Baldwin MR, Kim JJ, Barbieri JT (2011) Unique ganglioside binding by botulinum neurotoxins C and D-SA. FEBS J 278:4486-496
177. Engedal N, Skotland T, Torgersen ML, Sandvig K (2011) Shiga toxin and its use in targeted cancer therapy and imaging. Microb Biotechnol 4:32-6
178. Kovbasnjuk O, Mourtazina R, Baibakov B, Wang T, Elowsky C, Choti MA, Kane A, Donowitz M (2005) The glycosphingolipid globotriaosylceramide in the metastatic transformation of colon cancer. Proc Natl Acad Sci USA 102:19087-9092
179. Falguières T, Maak M, von Weyhern C, Sarr M, Sastre X, Poupon MF, Robine S, Johannes L, Janssen KP (2008) Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool. Mol Cancer Ther 7:2498-508
180. Distler U, Souady J, Hülsewig M, Drmi?-Hofman I, Haier J, Friedrich AW, Karch H, Senninger N, Dreisewerd K, Berkenkamp S, Schmidt MA, Peter-Katalini? J, Müthing J (2009) Shiga toxin receptor Gb3Cer/CD77: tumor association and promising therapeutic target in pancreas and colon cancer. PLoS One 4:e6813
181. Beddoe T, Paton AW, Le Nours J, Rossjohn J, Paton JC (2010) Structure, biological functions and applications of the AB5 toxins. Trends Biochem Sci 35:411-18
182. Hotz B, Backer MV, Backer JM, Buhr HJ, Hotz HG (2010) Specific targeting of tumor endothelial cells by Shiga-like toxin-vascular endothelial growth factor fusion protein as a novel treatment strategy for pancreatic cancer. Neoplasia 12:797-06
183. Maak M, Nitsche U, Keller L, Wolf P, Sarr M, Thiebaud M, Rosenberg R, Langer R, Kleeft J, Friess H, Johannes L, Janssen KP (2011) Tumor-specific targeting of pancreatic cancer with Shiga toxin B-subunit. Mol Cancer Ther 10:1918-928
184. Lingwood CA (1999) Glycolipid receptors for verotoxin and / Helicobacter pylori: role in pathology. Biochim Biophys Acta 1455:375-86
185. 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 276:42915-2922
186. Meisen I, Friedrich AW, Karch H, Witting U, Peter-Katalini? J, Müthing J (2005) Application of combined high-performance thin-layer chromatography immunostaining and nanoelectrospray ionization 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 19:3659-665
187. DeGrandis S, Law H, Brunton J, Gyles C, Lingwood CA (1989) Globotetraosylceramide is recognized by the pig edema disease toxin. J Biol Chem 264:12520-2525
188. Gillard BK, Jones MA, Marcus DM (1987) Glycosphingolipids of human umbilical vein endothelial cells and smooth muscle cells. Arch Biochem Biophys 256:435-45
189. Gillard BK, Jones MA, Turner AA, Lewis DE, Marcus DM (1990) Interferon-γ alters expression of endothelial cell-surface glycosphingolipids. Arch Biochem Biophys 279:122-29
190. Gillard BK, Heath JP, Thurmon LT, Marcus DM (1991) Association of glycosphingolipids with intermediate filaments of human umbilical vein endothelial cells. Exp Cell Res 192:433-44
191. Gillard BK, Thurmon LT, Marcus DM (1993) Variable subcellular localization of glycosphingolipids. Glycobiology 3:57-7
192. Müthing J, Duvar S, Heitmann D, Hanisch FG, Neumann U, Lochnit G, Geyer R, Peter-Katalini? J (1999) Isolation and structural characterization of glycosphingolipids of in vitro propagated human umbilical vein endothelial cells. Glycobiology 9:459-68
193. Okuda T, Nakakita SI, Nakayama KI (2010) Structural characterization and dynamics of globotetraosylceramide in vascular endothelial cells under TNF-α stimulation. Glycoconj J 27:287-96
194. Louise CB, Kaye SA, Boyd B, Lingwood CA, Obrig TG (1995) Shiga toxin-associated haemolytic uremic syndrome: effect of sodium butyrate on sensitivity of human umbilical vein endothelial cells to Shiga toxin. Infect Immun 63:2766-769
195. Müthing J (2000) Analyses of glycosphingolipids by high-performance liquid chromatography. Methods Enzymol 312:45-4
196. Müthing J (1996) High-resolution thin-layer chromatography of gangliosides. J Chromatogr A 720:3-5
197. Müthing J (1998) TLC in structure and recognition studies of glycosphingolipids. In: Hounsell EF (ed) Methods in molecular biology. Humana, Totawa, pp 183-95
198. Kannagi R (2000) Monoclonal anti-glycosphingolipid antibodies. Methods Enzymol 312:160-79
199. Nutikka A, Binnington-Boyd B, Lingwood CA (2003) Methods for the identification of host receptors for Shiga toxin. Methods Mol Med 73:197-08
200. Raa H, Grimmer S, Schwudke D, Bergan J, W?lchli S, Skotland T, Shevchenko A, Sandvig K (2009) Glycosphingolipid requirements for endosome-to-Golgi transport of Shiga toxin. Traffic 10:868-82
201. Lingwood CA, Manis A, Mahfoud R, Khan F, Binnington B, Mylvaganam M (2010) New aspects of the regulation of glycosphingolipid receptor function. Chem Phys Lipids 163:27-5
202. Lingwood CA, Binnington B, Manis A, Branch DR (2010) Globotriaosylceramide receptor function—where membrane structure and pathology intersect. FEBS Lett 584:1879-886
203. Robson WLM, Leung AKC, Montgomery MD (1991) Causes of death in hemolytic uremic syndrome. Child Nephrol Urol 11:228-33
204. Siegler RL (1994) Spectrum of extrarenal involvement in postdiarrheal hemolytic uremic syndrome. J Pediatr 125:511-18
205. Stins MF, Gilles F, Kim KS (1997) Selective expression of adhesion molecules on human brain microvascular endothelial cells. J Neuroimmunol 76:81-0
206. Schweppe CH, Bielaszewska M, Pohlentz G, Friedrich AW, Büntemeyer H, Schmidt MA, Kim KS, Peter-Katalini? J, Karch H, Müthing J (2008) Glycosphingolipids in vascular endothelial cells: relationship of heterogeneity in Gb3Cer/CD77 receptor expression with differential Shiga toxin 1 cytotoxicity. Glycoconj J 25:291-04
207. Pellizzari A, Pang H, Lingwood CA (1992) Binding of verocytotoxin 1 to its receptor is influenced by differences in receptor fatty acid content. Biochemistry 31:1363-370
208. Arab S, Lingwood CA (1996) Influence of phospholipid chain length on verotoxin/globotriaosylceramide binding in model membranes: comparison of a supported bilayer film and liposomes. Glycoconj J 13:159-66
209. Satchell SC, Tasman CH, Singh A, Ni L, Geelen J, von Ruhland CJ, O’Hare MJ, Saleem MA, van den Heuvel LP, Mathieson PW (2006) Conditionally immortalized human glomerular endothelial cells expressing fenestrations in response to VEGF. Kidney Int 69:1633-640
210. Betz J, Bauwens A, Kunsmann L, Bielaszewska M, Mormann M, Humpf HU, Karch H, Friedrich AW, Müthing J (2012) Uncommon membrane distribution of Shiga toxin glycosphingolipid receptors in toxin-sensitive human glomerular microvascular endothelial cells. Biol Chem 393:133-47
211. Kanda T, Ariga T, Kubodera H, Jin HL, Owada K, Kasama T, Yamawaki M, Mizusawa H (2004) Glycosphingolipid composition of primary cultured human brain microvascular endothelial cells. J Neurosci Res 78:141-50
212. Müthing J, Distler U (2010) Advances on the compositional analysis of glycosphingolipids combining thin-layer chromatography with mass spectrometry. Mass Spectrom Rev 29:425-79
213. Meisen I, Mormann M, Müthing J (2011) Thin-layer chromatography, overlay technique and mass spectrometry: a versatile triad advancing glycosphingolipidomics. Biochim Biophys Acta 1811:875-96
214. Meisen I, Peter-Katalini? J, Müthing J (2003) 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 75:5719-725
215. Meisen I, Peter-Katalini? J, Müthing J (2004) Direct analysis of silica gel extracts from immunostained glycosphingolipids by nanoelectrospray ionization quadrupole time-of-flight mass spectrometry. Anal Chem 76:2248-255
216. Hoffmann P, Hülsewig M, Duvar S, Ziehr H, Mormann M, Peter-Katalini? J, Friedrich AW, Karch H, Müthing J (2010) On the structural diversity of Shiga toxin glycosphingolipid receptors in lymphoid and myeloid cells determined by nanoelectrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 24:2295-304
217. Schweppe CH, Hoffmann P, Nofer JR, Pohlentz G, Mormann M, Karch H, Friedrich AW, Müthing J (2010) Neutral glycosphingolipids in human blood: a precise mass spectrometry analysis with special reference to lipoprotein-associated Shiga toxin receptors. J Lipid Res 51:2282-294
218. Edgell CJS, MacDonald CC, Graham JB (1983) Permanent cell line expressing human factor VIII-related antigen established by hybridizatíon. Proc Natl Acad Sci USA 80:3734-737
219. Domon B, Costello CE (1988) Structure elucidation of glycosphingolipids and gangliosides using high-performance tandem mass spectrometry. Biochemistry 27:1534-543
220. Domon B, Costello CE (1988) A systematic nomenclature for carbohydrate fragmentation in FAB-MS/MS spectra of glycoconjugates. Glycoconj J 5:397-09
221. Pust S, Dyve AB, Torgersen ML, van Deurs B, Sandvig K (2010) Interplay between toxin transport and flotillin localization. PLoS One 5:e8844
222. Brown DA, Rose KJ (1992) Sorting of GPI-anchored proteins to glycolipid enriched membrane subdomains during transport to the apical cell surface. Cell 68:533-44
223. Simons K, Gerl MJ (2010) Revitalizing membrane rafts: new tools and insights. Nat Rev Mol Cell Biol 11:688-99
224. Munro S (2003) Lipid rafts: elusive or illusive? Cell 115:377-88
225. Dietrich C, Yang B, Fujiwara T, Kusumi A, Jacobson K (2002) Relationship of lipid rafts to transient confinement zones detected by single particle tracking. Biophys J 82:274-84
226. Gaus K, Gratton E, Kable EPW, Jones AS, Gelissen I, Kritharides L, Jessup W (2003) Visualizing lipid raft structure and raft domains in living cells with two-photon microscopy. Proc Natl Acad Sci USA 100:15554-5559
227. Lagerholm BC, Weinreb GE, Jacobson K, Thompson NL (2005) Detecting microdomains in intact cell membranes. Annu Rev Phys Chem 56:309-36
228. Azuma R, Kitagawa T, Kobayashi H, Konogaya A (2006) Particle simulation approach for subcellular dynamics and interactions of biological molecules. BMC Bioinforma 7(Suppl 4):S20
229. Kahya N (2006) Targeting membrane proteins to liquid-ordered phases: molecular self-organization explored by fluorescence correlation spectroscopy. Chem Phys Lipids 141:158-68
230. Eggeling C, Ringemann C, Medda R, Schwarzmann G, Sandhoff K, Polyakova S, Belov VN, Hein B, von Middendorff C, Sch?nle A, Hell SW (2009) Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature 457:1159-162
231. Engel S, Scolari S, Thaa B, Krebs N, Korte T, Herrmann A, Veit M (2010) FLIM-FRET and FRAP reveal association of virus haemagglutinin with membrane rafts. Biochem J 425:567-73
232. Zhong J (2011) From simple to complex: investigating the effects of lipid composition and phase on the membrane interactions of biomolecules using in situ atomic force microscopy. Integr Biol 3:632-44
233. Bastos AE, Scolari S, St?ckl M, de Almeida RF (2012) Applications of fluorescence lifetime spectroscopy and imaging to lipid domains in vivo. Methods Enzymol 504:57-1
234. Lingwood D, Simons K (2010) Lipid rafts as a membrane-organizing principle. Science 327:46-0
235. Simons K, Sampaio JL (2011) Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol 3:a004697
236. Zaas DW, Duncan M, Wright JR, Abraham SN (2005) The role of lipid rafts in the pathogenesis of bacterial infections. Biochim Biophys Acta 746:305-13
237. Allen JA, Halverson-Tamboli RA, Rasenick MM (2007) Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci 8:128-40
238. Hanzal-Bayer MF, Hancock JF (2007) Lipid rafts and membrane traffic. FEBS Lett 581:2098-104
239. Vieira FS, Corrêa G, Einicker-Lamast M, Coutinho-Silva R (2010) Host-cell lipid rafts: a safe door for micro-organisms? Biol Cell 102:391-07
240. Fessler MB, Parks JS (2011) Intracellular lipid flux and membrane microdomains as organizing principles in inflammatory cell signaling. J Immunol 187:1529-535
241. Sonnino S, Prinetti A, Mauri L, Chigorno V, Tettamanti G (2006) Dynamic and structural properties of sphingolipids as driving forces for the formation of membrane domains. Chem Rev 106:2111-125
242. Sonnino S, Mauri L, Chigorno V, Prinetti A (2007) Gangliosides as components of lipid membrane domains. Glycobiology 17:1R-3R
243. Prinetti A, Loberto N, Chigorno V, Sonnino S (2009) Glycosphingolipid behaviour in complex membranes. Biochim Biophys Acta 1788:184-93
244. Pike LJ (2009) The challenge of lipid rafts. J Lipid Res 50:S323–S328
245. Gupta G, Surolia A (2010) Glycosphingolipids in microdomain formation and their spatial organization. FEBS Lett 584:1634-641
246. Maeda Y, Kinoshita T (2011) Structural remodeling, trafficking and functions of glycosylphosphatidylinositol-anchored proteins. Prog Lipid Res 50:411-24
247. Aicart-Ramos C, Valero RA, Rodriguez-Crespo I (2011) Protein palmitoylation and subcellular trafficking. Biochim Biophys Acta 1808:2981-994
248. Quinn PJ (2010) A lipid matrix model of membrane raft structure. Prog Lipid Res 49:390-06
249. Maggio B, Fanani ML, Rosetti CM, Wilke N (2006) Biophysics of sphingolipids II. Glycosphingolipids: an assortment of multiple structural information transducers at the membrane surface. Biochim Biophys Acta 1758:1922-944
250. Westerlund B, Slotte JP (2009) How the molecular features of glycosphingolipids affect domain formation in fluid membranes. Biochim Biophys Acta 1788:194-01
251. Hakomori SI (2002) The glycosynapse. Proc Natl Acad Sci USA 99:225-32
252. Hakomori SI (2000) Cell adhesion/recognition and signal transduction through glycosphingolipid microdomain. Glycoconj J 17:143-51
253. Todeschini AR, Hakomori SI (2008) Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta 1780:421-33
254. Hakomori SI (2010) Glycosynaptic microdomains controlling tumor cell phenotype through alteration of cell growth, adhesion, and mortality. FEBS Lett 584:1901-906
255. Fantini J, Maresca M, Hammache D, Yahi N, Delézay O (2000) Glycosphingolipid (GSL) microdomain 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 17:173-79
256. Kasahara K, Sanai Y (2000) Functional roles of glycosphingolipids in signal transduction via lipid rafts. Glycoconj J 17:153-62
257. Sorice M, Longo A, Garofalo T, Mattei V, Misasi R, Pavan A (2004) Role of GM3-enriched microdomains in signal transduction regulation in T lymphocytes. Glycoconj J 20:63-0
258. Sonnino S, Prinetti A, Nakayama H, Yangida M, Ogawa H, Iwabuchi K (2009) Role of very long fatty acid-containing glycosphingolipids in membrane organization and cell signaling: the model of lactosylceramide in neutrophils. Glycoconj J 26:615-21
259. Iwabuchi K, Nakayama H, Iwahara C, Takamori K (2010) Significance of glycosphingolipid fatty acid chain length on membrane microdomain-mediated signal transduction. FEBS Lett 584:1642-652
260. Yoshizaki F, Nakayama H, Iwahara C, Takamori K, Ogawa H, Iwabuchi K (2008) Role of glycosphingolipid-enriched microdomains in innate immunity: microdomain-dependent phagocytic cell functions. Biochim Biophys Acta 170:383-92
261. Schengrund CL (2010) Lipid rafts: keys to neurodegeneration. Brain Res Bull 82:7-7
262. Fantini J (2003) How sphingolipids bind and shape proteins: molecular basis of lipid–protein interactions in lipid shells, rafts and related biomembrane domains. Cell Mol Life Sci 60:1027-032
263. London E, Brown DA (2000) Insolubility of lipids in Triton X-100: physical origin and relationship to sphingolipid/cholesterol membrane domains (rafts). Biochim Biophys Acta 1508:182-95
264. Lingwood D, Simons K (2007) Detergent resistance as a tool in membrane research. Nat Protoc 2:2159-165
265. Brown DA (2006) Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology 21:430-39
266. Lichtenberg D, Goni FM, Heerklotz H (2005) Detergent-resistant membranes should not be identified with membrane rafts. Trends Biochem Sci 30:430-36
267. Sens P, Johannes L, Bassereau P (2008) Biophysical approaches to protein-induced membrane deformations in trafficking. Curr Opin Cell Biol 20:476-82
268. Safouane M, Berland L, Callan-Jones A, Sorre B, R?mer W, Johannes L, Toombes GES, Bassereau P (2010) Lipid cosorting mediated by Shiga toxin induced tubulation. Traffic 11:1519-529
269. Kovbasnjuk O, Edidin M, Donovitz M (2001) Role of lipid rafts in Shiga toxin 1 interaction with the apical surface of Caco-2 cells. J Cell Sci 114:4025-031
270. Hanashima T, Miyake M, Yahiro K, Iwamaru Y, Ando A, Morinaga N, Noda M (2008) Effect of Gb3 in lipid rafts in resistance to Shiga-like toxin of mutant Vero cells. Microb Pathog 45:124-33
271. Falguières T, Mallard F, Baron C, Hanau D, Lingwood C, Goud B, Salamero J, Johannes L (2001) Targeting of Shiga toxin B-subunit to retrograde transport route in association with detergent-resistant membranes. Mol Biol Cell 12:2453-468
272. Falguières T, R?mer W, Amessou M, Afonso C, Wolf C, Tabet JC, Lamaze C, Johannes L (2006) Functionally different pools of Shiga toxin receptor, globotriaosylceramide, in HeLa cells. FEBS J 273:5205-218
273. Smith DC, Sillence DJ, Falguières T, Jarvis RM, Johannes L, Lord JM, Platt FM, Roberts LM (2006) 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 17:1375-387
274. 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 globotriaosylceramide (Gb3Cer/CD77) in low density, detergent-insoluble microdomains. J Biol Chem 274:35278-5282
275. Takenouchi H, Kiyokawa N, Taguchi T, Matsui J, Katagiri YU, Okita H, Okuda K, Fujimoto J (2004) Shiga toxin binding to globotriaosylceramide induces intracellular signals that mediate cytoskeleton remodeling in human renal carcinoma-derived cells. J Cell Sci 117:3911-922
276. 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 216:750-63
277. Mafoud R, Manis A, Lingwood CA (2009) Fatty acid-dependent globotriaosylceramide receptor function in detergent resistant membranes. J Lipid Res 50:1744-755
278. Mafoud 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 285:36049-6059
279. Lingwood D, Binnington B, Róg T, Vattulainen I, Grzybek M, Coskun ü, Lingwood CA, Simons K (2011) Cholesterol modulates glycolipid conformation and receptor activity. Nat Chem Biol 7:260-62
280. Kenworthy A (2002) Peering inside lipid rafts and caveolae. Trends Biochem Sci 27:435-38
281. Michel V, Bakovic M (2007) Lipid rafts in health and disease. Biol Cell 99:129-40
282. Lajoie P, Nabi IR (2010) Lipid rafts, caveolae, and their endocytosis. Int Rev Cell Mol Biol 282:135-63
283. Anderson RGW (1998) The caveolae membrane system. Annu Rev Biochem 67:199-25
284. Frank PG, Woodman SE, Park DS, Lisanti MP (2003) Caveolin, caveolae, and endothelial cell function. Arterioscler Thromb Vasc Biol 23:1161-168
285. Cohen AW, Hnasko R, Schubert W, Lisanti MP (2004) Role of caveolae and caveolins in health and disease. Physiol Rev 84:1341-379
286. Li XA, Everson WV, Smart EJ (2005) Caveolae, lipid rafts, and vascular disease. Trends Cardiovasc Med 15:92-6
287. Mineo C, Shaul PW (2006) Circulating cardiovascular disease risk factors and signaling in endothelial cell caveolae. Cardiovasc Res 70:31-1
288. Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185-94
289. Hansen CG, Nichols BJ (2009) Molecular mechanisms of clathrin-independent endocytosis. J Cell Sci 122:1713-721
290. Hansen CG, Nichols BJ (2010) Exploring the caves: cavins, caveolins and caveolae. Trends Cell Biol 20:177-86
291. Chidlow JH Jr, Sessa WC (2010) Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. Cardiovasc Res 86:219-25
292. Sprenger RR, Fontijn RD, van Marl J, Pannekoek H, Horrevoets AJG (2006) Spatial segregation of transport and signalling functions between human endothelial caveolae and lipid raft proteomes. Biochem J 400:401-10
293. Anderson RGW, Jacobson K (2002) A role for lipid shells in targeting proteins to caveolae, rafts, and other lipid domains. Science 296:1821-825
294. Stan RV (2002) Structure and function of endothelial caveolae. Microsc Res Tech 57:350-64
295. Nabi IR, Le PU (2003) Caveolae/raft-dependent endocytosis. J Cell Biol 161:673-77
296. Parton RG, Richards AA (2003) Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms. Traffic 4:724-38
297. van Deurs B, Roepstorff K, Hommelgaard AM, Sandvig K (2003) Caveolae: anchored, multifunctional platforms in the lipid ocean. Trends Cell Biol 13:92-00
298. Hommelgaard AM, Roepstorff K, Vilhardt F, Torgersen ML, Sandvig K, van Deurs B (2005) Caveolae: stable membrane domains with a potential for internalization. Traffic 6:720-24
299. Lakhan SE, Sabharanjak S, De A (2009) Endocytosis of glycosylphosphatidylinositol-anchored proteins. J Biomed Sci 16:93
300. Cheng ZJ, Singh RD, Marks DL, Pagano RE (2006) Membrane microdomains, caveolae, and caveolar endocytosis of sphingolipids. Mol Membr Biol 23:101-10
301. Sonnino S, Prinetti A (2009) Sphingolipids and membrane environments for caveolin. FEBS Lett 583:597-06
302. Yu RK, Suzuki Y, Yanagisawa M (2010) Membrane glycolipids in stem cells. FEBS Lett 584:1694-699
303. Higashi N, Matsumura Y, Mizuno F, Kasahara K, Sugiura S, Mikasa K, Kita E (2010) Enhanced expression of ATP-binding cassette transporter A1 in non-rafts decreases the sensitivity of vascular endothelial cells to Shiga toxin. Microb Pathog 49:141-52
304. Paton JC, Paton AW (2006) Shiga toxin ‘goes retro-in human primary kidney cells. Kidney Int 70:2049-051
305. Khan F, Proulx F, Lingwood CA (2009) Detergent-resistant globotriaosylceramide may define verotoxin/glomeruli-restricted haemolytic uremic syndrome pathology. Kidney Int 75:1209-216
306. Betz J, Bielaszewska M, Thies A, Humpf HU, Dreisewerd K, Karch H, Kim KS, Friedrich AW, Müthing J (2011) Shiga toxin glycosphingolipid receptors in microvascular and macrovascular endothelial cells: differential association with membrane lipid raft microdomains. J Lipid Res 52:618-34
307. Scheiring J, Andreoli SP, Zimmerhackl LB (2008) Treatment and outcome of Shiga toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 23:1749-760
308. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI (2000) The risk of the hemolytic-uremic syndrome after antibiotic treatment of / Escherichia coli O157:H7 infections. N Eng J Med 342:1930-936
309. Serna A 4th, Boedeker EC (2008) Pathogenesis and treatment of Shiga toxin-producing / Escherichia coli infections. Curr Opin Gastroenterol 24:38-7
310. Mukhopadhyay S, Linstedt AD (2012) Manganese blocks intracellular trafficking of Shiga toxin and protects against Shiga toxicosis. Science 335:332-35
311. Bitzan M (2009) Treatment options for HUS secondary to / Escherichia coli O157:H7. Kidney Int 75:S62–S66
312. Bitzan M, Schaefer F, Reymond D (2010) Treatment of typical (enteropathic) hemolytic uremic syndrome. Semin Thromb Hemost 36:594-10
313. Paton AW, Morona R, Paton JC (2000) A new biological agent for treatment of Shiga toxigenic / Escherichia coli infections and dysentery in humans. Nat Med 6:265-70
314. Paton AW, Morona R, Paton JC (2001) Neutralization of Shiga toxins Stx1, Stx2c, and Stx2e by recombinant bacteria expressing mimics of globotriose and globotetraose. Infect Immun 69:1967-970
315. Jeong KI, Tzipori S, Sheoran AS (2010) Shiga toxin 2-specific but not Shiga toxin 1-specific human monoclonal antibody protects piglets challenged with enterohemorrhagic / Escherichia coli producing Shiga toxin 1 and Shiga toxin 2. J Infect Dis 201:1081-083
316. 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 cαStx2 administered intravenously to healthy adult volunteers. Antimicrob Agents Chemother 49:1808-812
317. Bitzan M, Poole R, Mehran M, Sicard E, Brockus C, Thuning-Roberson C, Rivière M (2009) Safety and pharmacokinetics of chimeric anti-Shiga toxin 1 and anti-Shiga toxin 2 monoclonal antibodies in healthy volunteers. Antimicrob Agents Chemother 53:3081-087
318. Kitov PI, Sadowska JM, Mulvey G, Armstrong GD, Ling H, Pannu NS, Read RJ, Bundle DR (2000) Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands. Nature 403:669-72
319. Williams SJ, Davies GJ (2001) Protein–carbohydrate interactions: learning lessons from nature. Trends Biotechnol 19:356-62
320. Mulvey GL, Marcato P, Kitov PI, Sadowska J, Bundle DR, Armstrong GD (2003) Assessment in mice of therapeutic potential of tailored, multivalent Shiga toxin carbohydrate ligands. J Infect Dis 187:640-49
321. Nishikawa K, Matsuoka K, Kita E, Okabe N, Mizuguchi M, Hino K, Miyazawa S, Yamasaki C, Aoki J, Takashima S, Yamakawa Y, Nishijima M, Terunuma D, Kuzuhara H, Natori Y (2002) A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing / Escherichia coli O157:H7. Proc Natl Acad Sci USA 99:7669-674
322. Karmali MA (2004) Prospects for preventing serious systemic toxemic complications of Shiga toxin producing / Escherichia coli infections using Shiga toxin receptor analogues. J Infect Dis 189:355-59
323. Watanabe M, Matsuoka K, Kita E, Igai K, Higashi N, Miyagawa A, Watanabe T, Yanoshita R, Samejima Y, Terunuma D, Natori Y, Nishikawa K (2004) Oral therapeutic agents with highly clustered globotriose for treatment of Shiga toxigenic / Escherichia coli infections. J Infect Dis 189:360-68
324. 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 191:2097-105
325. Clark GC, Basak AK, Titball RW (2007) The rational design of bacterial toxin inhibitors. Curr Comput Aided Drug Des 3:1-2
326. Trachtman H, Cnaan A, Christen E, Gibbs K, Zhao S, Acheson DWK, Weiss R, Kaskel FJ, Spitzer A, Hirschman GH (2003) Effect of an oral Shiga toxin-binding agent on diarrhea-associated hemolytic uremic syndrome in children. JAMA 290:1337-344
327. MacConnachie AA, Todd WT (2004) Potential therapeutic agents for the prevention and treatment of haemolytic uraemic syndrome in Shiga toxin producing / Escherichia coli infection. Curr Opin Infect Dis 17:479-82
328. Sharon N (2006) Carbohydrates as future anti-adhesion drugs for infectious diseases. Biochim Biophys Acta 1760:527-37
329. Thomas RJ (2010) Receptor mimicry as novel therapeutic treatment for biothreat agents. Bioeng Bugs 1:17-0
330. Kulkarni AA, Weiss AA, Iyer SS (2010) Glycan-based high-affinity ligands for toxins and pathogen receptors. Med Res Rev 30:327-93
331. Orth D, Khan AB, Naim A, Grif K, Brockmeyer J, Karch H, Joannidis M, Clark SJ, Day AJ, Fidanzi S, Stoiber H, Dierich MP, Zimmerhackl LB, Würzner R (2009) Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome. J Immunol 182:6349-400
332. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, Proulx F, Clermont MJ, Le Deist F, Niaudet P, Schaefer F (2011) Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med 364:2561-563
333. Orth-H?ller D, Riedl M, Würzner R (2011) Inhibition of terminal complement activation in severe Shiga toxin-associated HUS—perfect example for a fast track from bench to bedside. EMBO Mol Med 3:617-19
334. Lingwood CA (1994) Verotoxin-binding in human renal sections. Nephron 66:21-8
335. Kaneko K, Kiyokawa N, Ohtomo Y, Nagaoka R, Yamashiro Y, Taguchi T, Mori T, Fujimoto J, Takeda T (2001) Apoptosis of renal tubular cells in Shiga-toxin-mediated haemolytic uremic syndrome. Nephron 87:182-85
336. Creydt VP, Silberstein C, Zotta E, Ibarra C (2006) Cytotoxic effect of Shiga toxin-2 holotoxin and ist B subunit on human renal tubular epithelial cells. Microbes Infect 8:410-19
337. Silberstein C, Creydt VP, Gerhardt E, Nú?ez P, Ibarra C (2008) Inhibition of water absorption in human proximal tubular epithelial cells in response to Shiga toxin-2. Pediatr Nephrol 23:1981-990
338. 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 79:3527-540
339. van Setten PA, van Hinsbergh VWM, van den Heuvel LPWJ, van der Velden TJAN, van de Kar NCAJ, Krebbers RJM, Karmali MA, Monnens LAH (1997) Verocytotoxin inhibits mitogenesis and protein synthesis in purified human glomerular mesangial cells without affecting cell viability: evidence for two distinct mechanisms. J Am Soc Nephrol 8:1877-888
340. Simon M, Cleary TG, Hernandez JD, Abboud HE (1998) Shiga toxin 1 elicits diverse biologic responses in mesangial cells. Kidney Int 54:1117-127
341. Ren J, Utsunomiya I, Taguchi K, Ariga T, Tai T, Ihara Y, Miyatake T (1999) Localization of verotoxin receptors in nervous system. Brain Res 825:183-88
342. Obata F, Tohyama K, Bonev AD, Kolling GL, Keepers TR, Gross LK, Nelson MT, Sato S, Obrig TG (2008) Shiga toxin 2 affects the central nervous system through receptor globotriaosylceramide localized to neurons. J Infect Dis 198:1398-406
343. Arab S, Murakami M, Dirks P, Boyd B, Hubbard SL, Lingwood CA, Rutka JT (1998) Verotoxins inhibit the growth of and induce apoptosis in human astrocytoma cells. J Neurooncol 40:137-50
344. Arab S, Rutka J, Lingwood C (1999) Verotoxin induces apoptosis and the complete, rapid, long-term elimination of human astrocytoma xenografts in nude mice. Oncol Res 11:33-9
345. Salhia B, Rutka JT, Lingwood C, Nutikka A, van Furth WR (2002) The treatment of malignant meningioma with verotoxin. Neoplasia 4:304-11
346. Johansson D, Johansson A, Grankvist K, Andersson U, Henriksson R, Bergstr?m P, Br?nnstr?m T, Behnam-Motlagh P (2006) Verotoxin-1 induction of apoptosis in Gb3-expressing human glioma cell lines. Cancer Biol Ther 5:1211-217
347. Jinadasa RN, Bloom SE, Weiss RS, Duhamel GE (2011) Cytolethal distending toxin: a conserved bacetrial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages. Microbiology 157:1851-875
348. Schmidt H, Benz R (2003) Detection and characterization of EHEC-hemolysin. Methods Mol Med 73:151-63
349. Paton AW, And Paton JC (2010) / Escherichia coli subtilase cytotoxin. Toxins 2:215-28
350. Bielaszewska M, Sinha B, Kuczius T, Karch H (2005) 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 73:552-62
351. Friedrich AW, Lu S, Bielaszewska M, Prager R, Bruns P, Xu JG, Tsch?pe H, Karch H (2006) Cytolethal distending toxin in / Escherichia coli O157:H7: spectrum of conservation, structure, and endothelial toxicity. J Clin Microbiol 44:1844-846
352. Bielaszewska M, Stoewe F, Fruth A, Zhang W, Prager R, Brockmeyer J, Mellmann A, Karch H, Friedrich AW (2009) Shiga toxin, cytolethal distending toxin, and hemolysin repertoires in clinical / Escherichia coli O91 isolates. J Clin Microbiol 47:2061-066
353. Aldick T, Bielaszewska M, Zhang W, Brockmeyer J, Schmidt H, Friedrich AW, Kim KS, Schmidt MA, Karch H (2007) Hemolysin from Shiga toxin-negative / Escherichia coli O26 strains injures microvascular endothelium. Microbes Infect 9:282-90
354. Aldick T, Bielaszewska M, Uhlin BE, Humpf HU, Wai SN, Karch H (2009) Vesicular stabilization and activity augmentation of enterohaemorrhagic / Escherichia coli haemolyisn. Mol Microbiol 71:1496-508
355. Brockmeyer J, Aldick T, Soltwisch J, Zhang W, Tarr PI, Weiss A, Dreisewerd K, Müthing J, Bielaszewska M, Karch H (2011) Enterohaemorrhagic / Escherichia coli haemolysin is cleaved and inactivated by serine protease EspPα. Environ Microbiol 13:1327-341
356. Furukawa T, Yahiro K, Tsuji AB, Terasaki Y, Morinaga N, Miyazaki M, Fukuda Y, Saga T, Moss J, Noda M (2011) Fatal hemorrhage induced by subtilase cytotoxin from Shiga-toxigenic / Escherichia coli. Microb Pathog 50:159-67
357. Varki A (2001) Loss of / N-glycolylneuraminic acid in humans: mechanisms, consequences, and implications for hominid evolution. Am J Phys Anthropol (Suppl 33):54-9
358. Wang H, Paton JC, Thorpe CM, Bonder CS, Sun WY, Paton AW (2010) Tissue factor-dependent procoagulant activity of subtilase cytotoxin, a potent AB5 toxin produced by Shiga toxigenic / Escherichia coli. J Infect Dis 202:1415-423
359. Byres E, Paton AW, Paton JC, L?fling JC, Smith DF, Wilce MCJ, Talbot UM, Chong DC, Yu H, Huang S, Chen X, Varki NM, Varki A (2008) Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin. Nature 456:648-52
360. L?fling JC, Paton AW, Varki NM, Paton JC, Varki A (2009) A dietary non-human sialic acid may facilitate hemolytic-uremic syndrome. Kidney Int 76:140-44
361. Varki A (2007) Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins. Nature 446:1023-029
362. Raman R, Venkataraman M, Ramakrishnan S, Lang W, Raguram S, Sasisekharan R (2006) Advancing glycomics: implementation strategies at the consortium for functional glycomics. Glycobiology 16:82R-0R - 作者单位：Andreas Bauwens (1)
Josefine Betz (1)
Iris Meisen (1) (2)
Bj?rn Kemper (3)
Helge Karch (1)
Johannes Müthing (1) (2)
1. Institute for Hygiene, University of Münster, Robert-Koch-Str. 41, 48149, Münster, Germany
2. Interdisciplinary Center for Clinical Research, University of Münster, Domagkstr. 3, 48149, Münster, Germany
3. Center for Biomedical Optics and Photonics, University of Münster, Robert-Koch-Str. 45, 48149, Münster, Germany - ISSN：1420-9071
文摘
The two major Shiga toxin (Stx) types, Stx1 and Stx2, produced by enterohemorrhagic Escherichia coli (EHEC) in particular injure renal and cerebral microvascular endothelial cells after transfer from the human intestine into the circulation. Stxs are AB5 toxins composed of an enzymatically active A subunit and the pentameric B subunit, which preferentially binds to the glycosphingolipid globotriaosylceramide (Gb3Cer/CD77). This review summarizes the current knowledge on Stx-caused cellular injury and the structural diversity of Stx receptors as well as the initial molecular interaction of Stxs with the human endothelium of different vascular beds. The varying lipoforms of Stx receptors and their spatial organization in lipid rafts suggest a central role in different modes of receptor-mediated endocytosis and intracellular destiny of the toxins. The design and development of tailored Stx neutralizers targeting the oligosaccharide–toxin recognition event has become a very real prospect to ameliorate or prevent life-threatening renal and neurological complications.