A Novel Mechanism of Bacterial Toxin Transfer within Host Blood Cell-Derived Microvesicles

English version České info

Shiga toxin-producing enterohemorrhagic Escherichia coli are non-invasive bacteria that, after ingestion, cause disease by systemic release of toxins and other virulence factors. These infections cause high morbidity, including hemolytic uremic syndrome with severe anemia, low platelet counts, renal failure, and mortality. The most common clinical isolate is E. coli O157:H7. In 2011 an E. coli O104:H4 strain caused a large outbreak in Europe with high mortality. After Shiga toxin damages intestinal cells it comes in contact with blood cells and thus gains access to the circulation. In this study we have shown that the toxin is released into circulating host blood cell-derived microvesicles, in which it retains its toxicity but evades the host immune response. Our results suggest that these microvesicles can enter target organ cells in the kidney and transfer toxin into these cells as well as between cells. Such a mechanism of virulence has not been previously described in bacterial infection.

Vyšlo v časopise: A Novel Mechanism of Bacterial Toxin Transfer within Host Blood Cell-Derived Microvesicles. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004619
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004619

Souhrn

Zdroje

1. McKee ML, O'Brien AD (1995) Investigation of enterohemorrhagic Escherichia coli O157:H7 adherence characteristics and invasion potential reveals a new attachment pattern shared by intestinal E. coli. Infect Immun 63: 2070–2074. 7537254

2. Habib R (1992) Pathology of the Hemolytic Uremic Syndrome. In: Kaplan BS, Trompeter R.S., Moake J.L., editor. Hemolytic Uremic Syndrome and Thrombotic thrombocytopenic purpura. New York: Marcel Dekker Inc. 1300882

3. Karpman D, Håkansson A, Perez MT, Isaksson C, Carlemalm E, et al. (1998) Apoptosis of renal cortical cells in the hemolytic-uremic syndrome: in vivo and in vitro studies. Infect Immun 66: 636–644. 9453620

4. Wadolkowski EA, Sung LM, Burris JA, Samuel JE, O'Brien AD (1990) Acute renal tubular necrosis and death of mice orally infected with Escherichia coli strains that produce Shiga-like toxin type II. Infect Immun 58: 3959–3965. 2254023

5. Karpman D, Connell H, Svensson M, Scheutz F, Alm P, et al. (1997) The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection. J Infect Dis 175: 611–620. 9041333

6. Chromek M, Arvidsson I, Karpman D (2012) The antimicrobial peptide cathelicidin protects mice from Escherichia coli O157:H7-mediated disease. PLoS One 7: e46476. doi: 10.1371/journal.pone.0046476 23077510

7. Psotka MA, Obata F, Kolling GL, Gross LK, Saleem MA, et al. (2009) Shiga toxin 2 targets the murine renal collecting duct epithelium. Infect Immun 77: 959–969. doi: 10.1128/IAI.00679-08 19124603

8. Calderon Toledo C, Rogers TJ, Svensson M, Tati R, Fischer H, et al. (2008) Shiga toxin-mediated disease in MyD88-deficient mice infected with Escherichia coli O157:H7. Am J Pathol 173: 1428–1439. doi: 10.2353/ajpath.2008.071218 18832584

9. Békássy ZD, Calderon Toledo C, Leoj G, Kristoffersson A, Leopold SR, et al. (2011) Intestinal damage in enterohemorrhagic Escherichia coli infection. Pediatr Nephrol 26: 2059–2071. doi: 10.1007/s00467-010-1616-9 20809220

10. Lindberg AA, Brown JE, Strömberg N, Westling-Ryd M, Schultz JE, et al. (1987) Identification of the carbohydrate receptor for Shiga toxin produced by Shigella dysenteriae type 1. J Biol Chem 262: 1779–1785. 3543013

11. Sandvig K, Garred O, Prydz K, Kozlov JV, Hansen SH, et al. (1992) Retrograde transport of endocytosed Shiga toxin to the endoplasmic reticulum. Nature 358: 510–512. 1641040

12. Endo Y, Tsurugi K, Yutsudo T, Takeda Y, Ogasawara T, et al. (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: 45–50. 3276522

13. Waddell T, Cohen A, Lingwood CA (1990) Induction of verotoxin sensitivity in receptor-deficient cell lines using the receptor glycolipid globotriosylceramide. Proc Natl Acad Sci U S A 87: 7898–7901. 2236008

14. Chark D, Nutikka A, Trusevych N, Kuzmina J, Lingwood C (2004) Differential carbohydrate epitope recognition of globotriaosyl ceramide by verotoxins and a monoclonal antibody. Eur J Biochem 271: 405–417. 14717708

15. Jacewicz MS, Mobassaleh M, Gross SK, Balasubramanian KA, Daniel PF, et al. (1994) Pathogenesis of Shigella diarrhea: XVII. A mammalian cell membrane glycolipid, Gb3, is required but not sufficient to confer sensitivity to Shiga toxin. J Infect Dis 169: 538–546. 8158025

16. Khan F, Proulx F, Lingwood CA (2009) Detergent-resistant globotriaosyl ceramide may define verotoxin/glomeruli-restricted hemolytic uremic syndrome pathology. Kidney Int 75: 1209–1216. doi: 10.1038/ki.2009.7 19212418

17. Schüller S, Frankel G, Phillips AD (2004) Interaction of Shiga toxin from Escherichia coli with human intestinal epithelial cell lines and explants: Stx2 induces epithelial damage in organ culture. Cell Microbiol 6: 289–301. 14764112

18. Petruzziello-Pellegrini TN, Yuen DA, Page AV, Patel S, Soltyk AM, et al. (2012) The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin-associated hemolytic uremic syndrome in humans and mice. J Clin Invest 122: 759–776. doi: 10.1172/JCI57313 22232208

19. Morigi M, Galbusera M, Gastoldi S, Locatelli M, Buelli S, et al. (2011) Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J Immunol 187: 172–180. doi: 10.4049/jimmunol.1100491 21642543

20. Keepers TR, Psotka MA, Gross LK, Obrig TG (2006) A murine model of HUS: Shiga toxin with lipopolysaccharide mimics the renal damage and physiologic response of human disease. J Am Soc Nephrol 17: 3404–3414. 17082244

21. Brigotti M, Tazzari PL, Ravanelli E, Carnicelli D, Rocchi L, et al. (2011) Clinical relevance of shiga toxin concentrations in the blood of patients with hemolytic uremic syndrome. Pediatr Infect Dis J 30: 486–490. doi: 10.1097/INF.0b013e3182074d22 21164386

22. Ståhl AL, Sartz L, Nelsson A, Békássy ZD, Karpman D (2009) Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome. PLoS One 4: e6990. doi: 10.1371/journal.pone.0006990 19750223

23. Brigotti M, Caprioli A, Tozzi AE, Tazzari PL, Ricci F, et al. (2006) Shiga toxins present in the gut and in the polymorphonuclear leukocytes circulating in the blood of children with hemolytic-uremic syndrome. J Clin Microbiol 44: 313–317. 16455876

24. Brigotti M, Tazzari PL, Ravanelli E, Carnicelli D, Barbieri S, et al. (2010) Endothelial damage induced by Shiga toxins delivered by neutrophils during transmigration. J Leukoc Biol 88: 201–210. doi: 10.1189/jlb.0709475 20371598

25. te Loo DM, Monnens LA, van Der Velden TJ, Vermeer MA, Preyers F, et al. (2000) Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome. Blood 95: 3396–3402. 10828021

26. Karpman D, Papadopoulou D, Nilsson K, Sjögren AC, Mikaelsson C, et al. (2001) Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome. Blood 97: 3100–3108. 11342436

27. Ståhl AL, Sartz L, Karpman D (2011) Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Blood 117: 5503–5513. doi: 10.1182/blood-2010-09-309161 21447825

28. Hugel B, Martinez MC, Kunzelmann C, Freyssinet JM (2005) Membrane microparticles: two sides of the coin. Physiology (Bethesda) 20: 22–27.

29. Simak J, Gelderman MP (2006) Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers. Transfus Med Rev 20: 1–26. 16373184

30. Mack M, Kleinschmidt A, Bruhl H, Klier C, Nelson PJ, et al. (2000) Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat Med 6: 769–775. 10888925

31. Rozmyslowicz T, Majka M, Kijowski J, Murphy SL, Conover DO, et al. (2003) Platelet- and megakaryocyte-derived microparticles transfer CXCR4 receptor to CXCR4-null cells and make them susceptible to infection by X4-HIV. AIDS 17: 33–42. 12478067

32. Mause SF, von Hundelshausen P, Zernecke A, Koenen RR, Weber C (2005) Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler Thromb Vasc Biol 25: 1512–1518. 15890969

33. Risitano A, Beaulieu LM, Vitseva O, Freedman JE (2012) Platelets and platelet-like particles mediate intercellular RNA transfer. Blood 119: 6288–6295. doi: 10.1182/blood-2011-12-396440 22596260

34. Diehl P, Fricke A, Sander L, Stamm J, Bassler N, et al. (2012) Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 93: 633–644. doi: 10.1093/cvr/cvs007 22258631

35. Ge S, Hertel B, Emden SH, Beneke J, Menne J, et al. (2012) Microparticle generation and leucocyte death in Shiga toxin-mediated HUS. Nephrol Dial Transplant 27: 2768–2775. doi: 10.1093/ndt/gfr748 22234918

36. Meckes DG Jr., Raab-Traub N (2011) Microvesicles and viral infection. J Virol 85: 12844–12854. doi: 10.1128/JVI.05853-11 21976651

37. Bauwens A, Betz J, Meisen I, Kemper B, Karch H, et al. (2013) Facing glycosphingolipid-Shiga toxin interaction: dire straits for endothelial cells of the human vasculature. Cell Mol Life Sci 70: 425–457. doi: 10.1007/s00018-012-1060-z 22766973

38. Okuda T, Tokuda N, Numata S, Ito M, Ohta M, et al. (2006) Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins. J Biol Chem 281: 10230–10235. 16476743

39. Schüller S (2011) Shiga toxin interaction with human intestinal epithelium. Toxins (Basel) 3: 626–639. doi: 10.3390/toxins3060626 22069729

40. Malyukova I, Murray KF, Zhu C, Boedeker E, Kane A, et al. (2009) Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis. Am J Physiol Gastrointest Liver Physiol 296: G78–92. doi: 10.1152/ajpgi.90347.2008 18974311

41. Griener TP, Mulvey GL, Marcato P, Armstrong GD (2007) Differential binding of Shiga toxin 2 to human and murine neutrophils. J Med Microbiol 56: 1423–1430. 17965340

42. Arfilli V, Carnicelli D, Rocchi L, Ricci F, Pagliaro P, et al. (2010) Shiga toxin 1 and ricin A chain bind to human polymorphonuclear leucocytes through a common receptor. Biochem J 432: 173–180. doi: 10.1042/BJ20100455 20809900

43. Cooling LL, Walker KE, Gille T, Koerner TA (1998) Shiga toxin binds human platelets via globotriaosylceramide (Pk antigen) and a novel platelet glycosphingolipid. Infect Immun 66: 4355–4366. 9712788

44. van Setten PA, Monnens LA, Verstraten RG, van den Heuvel LP, van Hinsbergh VW (1996) Effects of verocytotoxin-1 on nonadherent human monocytes: binding characteristics, protein synthesis, and induction of cytokine release. Blood 88: 174–183. 8704172

45. Bitzan M, Richardson S, Huang C, Boyd B, Petric M, et al. (1994) Evidence that verotoxins (Shiga-like toxins) from Escherichia coli bind to P blood group antigens of human erythrocytes in vitro. Infect Immun 62: 3337–3347. 8039905

46. Fontaine A, Arondel J, Sansonetti PJ (1988) Role of Shiga toxin in the pathogenesis of bacillary dysentery, studied by using a Tox- mutant of Shigella dysenteriae 1. Infect Immun 56: 3099–3109. 3053452

47. Ståhl AL, Svensson M, Mörgelin M, Svanborg C, Tarr PI, et al. (2006) Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood 108: 167–176. 16514062

48. te Loo DM, Heuvelink AE, de Boer E, Nauta J, van der Walle J, et al. (2001) Vero cytotoxin binding to polymorphonuclear leukocytes among households with children with hemolytic uremic syndrome. J Infect Dis 184: 446–450. 11471102

49. te Loo DM, van Hinsbergh VW, van den Heuvel LP, Monnens LA (2001) Detection of verocytotoxin bound to circulating polymorphonuclear leukocytes of patients with hemolytic uremic syndrome. J Am Soc Nephrol 12: 800–806. 11274241

50. Brigotti M, Carnicelli D, Arfilli V, Tamassia N, Borsetti F, et al. (2013) Identification of TLR4 as the receptor that recognizes Shiga toxins in human neutrophils. J Immunol 191: 4748–4758. doi: 10.4049/jimmunol.1300122 24068665

51. Falguieres T, Mallard F, Baron C, Hanau D, Lingwood C, et al. (2001) Targeting of Shiga toxin B-subunit to retrograde transport route in association with detergent-resistant membranes. Mol Biol Cell 12: 2453–2468. 11514628

52. Morel O, Jesel L, Freyssinet JM, Toti F (2011) Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 31: 15–26. doi: 10.1161/ATVBAHA.109.200956 21160064

53. Karmali MA, Petric M, Lim C, Fleming PC, Arbus GS, et al. (1985) The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis 151: 775–782. 3886804

54. Caprioli A, Luzzi I, Rosmini F, Pasquini P, Cirrincione R, et al. (1992) Hemolytic-uremic syndrome and Vero cytotoxin-producing Escherichia coli infection in Italy. The HUS Italian Study Group. J Infect Dis 166: 154–158. 1607689

55. Porubsky S, Federico G, Muthing J, Jennemann R, Gretz N, et al. (2014) Direct acute tubular damage contributes to Shiga toxin-mediated kidney failure. J Pathol 234: 120–133. doi: 10.1002/path.4388 24909663

56. Owens AP 3rd, Mackman N (2011) Microparticles in hemostasis and thrombosis. Circ Res 108: 1284–1297. doi: 10.1161/CIRCRESAHA.110.233056 21566224

57. Müller I, Klocke A, Alex M, Kotzsch M, Luther T, et al. (2003) Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets. FASEB J 17: 476–478. 12514112

58. Galli M, Grassi A, Barbui T (1996) Platelet-derived microvesicles in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Thromb Haemost 75: 427–431. 8701402

59. Karpman D, Manea M, Vaziri-Sani F, Ståhl AL, Kristoffersson AC (2006) Platelet activation in hemolytic uremic syndrome. Semin Thromb Hemost 32: 128–145. 16575688

60. Calderon Toledo C, Arvidsson I, Karpman D (2011) Cross-reactive protection against enterohemorrhagic Escherichia coli infection by enteropathogenic E. coli in a mouse model. Infect Immun 79: 2224–2233. doi: 10.1128/IAI.01024-10 21402761

61. Gagnon M, Kheadr EE, Dabour N, Richard D, Fliss I (2006) Effect of Bifidobacterium thermacidophilum probiotic feeding on enterohemorrhagic Escherichia coli O157:H7 infection in BALB/c mice. Int J Food Microbiol 111: 26–33. 16822570

62. Palermo M, Alves-Rosa F, Rubel C, Fernandez GC, Fernandez-Alonso G, et al. (2000) Pretreatment of mice with lipopolysaccharide (LPS) or IL-1beta exerts dose-dependent opposite effects on Shiga toxin-2 lethality. Clin Exp Immunol 119: 77–83. 10606967

63. Stirling JW, Graff PS (1995) Antigen unmasking for immunoelectron microscopy: labeling is improved by treating with sodium ethoxide or sodium metaperiodate, then heating on retrieval medium. J Histochem Cytochem 43: 115–123. 7529784

64. Stone SM, Thorpe CM, Ahluwalia A, Rogers AB, Obata F, et al. (2012) Shiga toxin 2-induced intestinal pathology in infant rabbits is A-subunit dependent and responsive to the tyrosine kinase and potential ZAK inhibitor imatinib. Front Cell Infect Microbiol 135: 1–11.

65. Satchell SC, Tasman CH, Singh A, Ni L, Geelen J, et al. (2006) Conditionally immortalized human glomerular endothelial cells expressing fenestrations in response to VEGF. Kidney Int 69: 1633–1640. 16557232

66. Petric M, Karmali MA, Arbus GS, Roscoe M, Louie S, et al. (1987) Effects of cycloheximide and puromycin on cytotoxic activity of Escherichia coli verocytotoxin (Shiga-like toxin). J Clin Microbiol 25: 1265–1268. 3301891

67. Gentry MK, Dalrymple JM (1980) Quantitative microtiter cytotoxicity assay for Shigella toxin. J Clin Microbiol 12: 361–366. 7012172