The Effect of Bacterial Toxins on Platelet Function

  • Steven Kerrigan
  • Dermot CoxEmail author


While the ability of cell wall components of bacteria to interact with platelets has been well established there is also evidence that bacterial toxins have the potential to activate platelets. In particular pore-forming toxins such as pneumolysin, streptolysins and a-toxin can activate platelets probably in a manner similar to the calcium ionophore A23187. Cell wall components such as lipopolysaccharide and lipoteichoic acid can activate platelets via Toll-like receptors although evidence would suggest that this may be indirectly via leucocyte activation. Also, toxins such as Shiga toxin, superantigens, gingipains and M proteins can activate platelets. Ultimately the response of platelets to infection is likely to be due to both direct interaction with bacteria and exposure to secreted bacterial products.


Platelet Activation Necrotizing Fasciitis Toxic Shock Syndrome Bacterial Toxin Shiga Toxin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Anderson, R., Steel, H.C., Cockeran, R., von Gottberg, A., de Gouveia, L., Klugman, K.P., Mitchell, T.J., Feldman, C., 2007. Comparison of the effects of macrolides, amoxicillin, ceftriaxone, doxycycline, tobramycin and fluoroquinolones, on the production of pneumolysin by Streptococcus pneumoniae in vitro. J. Antimicrob. Chemother. 60, 1155–1158.PubMedCrossRefGoogle Scholar
  2. Andonegui, G., Kerfoot, S.M., McNagny, K., Ebbert, K.V.J., Patel, K.D., Kubes, P., 2005. Platelets express functional Toll-like receptor-4. Blood 106, 2417–2423.PubMedCrossRefGoogle Scholar
  3. Arvand, M., Bhakdi, S., Dahlback, B., Preissner, K.T., 1990. Staphylococcus aureus alpha-toxin attack on human platelets promotes assembly of the prothrombinase complex. J. Biol. Chem. 265, 14377–14381.PubMedGoogle Scholar
  4. Ashbaugh, C.D., Alberti, S., Wessels, M.R., 1998. Molecular analysis of the capsule gene region of group A Streptococcus: the has AB genes are sufficient for capsule expression. J. Bacteriol. 180, 4955–4959.PubMedGoogle Scholar
  5. Aslam, R., Speck, E.R., Kim, M., Crow, A.R., Bang, K.W.A., Nestel, F.P., Ni, H., Lazarus, A.H., Freedman, J., Semple, J.W., 2006. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo. Blood 107, 637–641.PubMedCrossRefGoogle Scholar
  6. Baliakina, E.V., Gerasimovskaia, E.V., Romanov, Iu.A., Atakhanov, Sh.E., 1999. Role of Staphylococcus aureus hemolytic toxin-alpha in pathogenesis of infectious endocarditis: studies in vitro. Ter. Arkh. 71, 28–31.PubMedGoogle Scholar
  7. Bayer, A.S., Ramos, M.D., Menzies, B.E., Yeaman, M.R., Shen, A.J., Cheung, A.L., 1997. Hyperproduction of alpha-toxin by Staphylococcus aureus results in paradoxically reduced virulence in experimental endocarditis: a host defense role for platelet microbicidal proteins. Infect. Immun. 65, 4652–4660.PubMedGoogle Scholar
  8. Benton, K.A., Paton, J.C., Briles, D.E., 1997. Differences in virulence for mice among Streptococcus pneumoniae strains of capsular types 2, 3, 4, 5, and 6 are not attributable to differences in pneumolysin production. Infect. Immun. 65, 1237–1244.PubMedGoogle Scholar
  9. Berg, M., Offermanns, S., Seifert, R., Schultz, G., 1994. Synthetic lipopeptide Pam3CysSer(Lys)4 is an effective activator of human platelets. Am. J. Physiol. Cell Physiol. 266, C1684–1691.Google Scholar
  10. Bernheimer, A.W., 1965. Staphylococcal alpha toxin. Ann. N.Y. Acad. Sci. 128, 112–123.PubMedCrossRefGoogle Scholar
  11. Bernheimer, A.W., Schwartz, L.L., 1965. Effect of staphylococcal and other bacterial toxins on platelets in vitro. J. Pathol. Bacteriol. 89, 209–223.PubMedCrossRefGoogle Scholar
  12. Berry, A.M., Paton, J.C., Hansman, D., 1992. Effect of insertional inactivation of the genes encoding pneumolysin and autolysin on the virulence of Streptococcus pneumoniae type 3. Microb. Pathog. 12, 87–93.PubMedCrossRefGoogle Scholar
  13. Berry, A.M., Yother, J., Briles, D.E., Hansman, D., Paton, J.C., 1989. Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect. Immun. 57, 2037–2042.PubMedGoogle Scholar
  14. Beutler, B., Hoebe, K., Du, X., Ulevitch, R.J., 2003. How we detect microbes and respond to them: the Toll-like receptors and their transducers. J. Leukoc. Biol. 74, 479–485.PubMedCrossRefGoogle Scholar
  15. Bhakdi, S., Bayley, H., Valeva, A., Walev, I., Walker, B., Kehoe, M., Palmer, M., 1996. Staphylococcal alpha-toxin, streptolysin-O, and Escherichia coli hemolysin: prototypes of pore-forming bacterial cytolysins. Arch. Microbiol. 165, 73–79.PubMedCrossRefGoogle Scholar
  16. Bhakdi, S., Tranum-Jensen, J., Sziegoleit, A., 1985. Mechanism of membrane damage by streptolysin-O. Infect. Immun. 47, 52–60.PubMedGoogle Scholar
  17. Bisno, A.L., Stevens, D.L., 1996. Streptococcal infections of skin and soft tissues. N. Engl. J. Med. 334, 240–245.PubMedCrossRefGoogle Scholar
  18. Bryant, A.E., Bayer, C.R., Chen, R.Y., Guth, P.H., Wallace, R.J., Stevens, D.L., 2005. Vascular dysfunction and ischemic destruction of tissue in Streptococcus pyogenes infection: the role of streptolysin O-induced platelet/neutrophil complexes. J. Infect. Dis. 192, 1014–1022.PubMedCrossRefGoogle Scholar
  19. Carapetis, J.R., Steer, A.C., Mulholland, E.K., Weber, M., 2005. The global burden of group A streptococcal diseases. Lancet Infect. Dis. 5, 685–694.PubMedCrossRefGoogle Scholar
  20. Charpentier, E., Tuomanen, E., 2000. Mechanisms of antibiotic resistance and tolerance in Streptococcus pneumoniae. Microbes Infect. 2, 1855–1864.PubMedCrossRefGoogle Scholar
  21. Clark, S.R., Ma, A.C., Tavener, S.A., McDonald, B., Goodarzi, Z., Kelly, M.M., Patel, K.D., Chakrabarti, S., McAvoy, E., Sinclair, G.D., Keys, E.M., Allen-Vercoe, E., Devinney, R., Doig, C.J., Green, F.H., Kubes, P., 2007. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 13, 463–469.PubMedCrossRefGoogle Scholar
  22. Cockeran, R., Durandt, C., Feldman, C., Mitchell, T.J., Anderson, R., 2002. Pneumolysin activates the synthesis and release of interleukin-8 by human neutrophils in vitro. J. Infect. Dis. 186, 562–565.PubMedCrossRefGoogle Scholar
  23. Cockerill, F.R., Hughes, J.G., Vetter, E.A., Mueller, R.A., Weaver, A.L., Ilstrup, D.M., Rosenblatt, J.E., Wilson, W.R., 1997. Analysis of 281,797 consecutive blood cultures performed over an eight-year period: trends in microorganisms isolated and the value of anaerobic culture of blood. Clin. Infect. Dis. 24, 403–418.PubMedCrossRefGoogle Scholar
  24. Cognasse, F., Hamzeh, H., Chavarin, P., Acquart, S., Genin, C., Garraud, O., 2005. Evidence of Toll-like receptor molecules on human platelets. Immunol. Cell Biol. 83, 196–198.PubMedCrossRefGoogle Scholar
  25. Cooling, L.L.W., Walker, K.E., Gille, T., Koerner, T.A.W., 1998. Shiga toxin binds human platelets via globotriaosylceramide (Pk Antigen) and a novel platelet glycosphingolipid. Infect. Immun. 66, 4355–4366.PubMedGoogle Scholar
  26. Corey, G.R., 2009. Staphylococcus aureus bloodstream infections: definitions and treatment. Clin. Infect. Dis. 48(Suppl 4), S254–S259.PubMedCrossRefGoogle Scholar
  27. Csako, G., Suba, E., Elin, R., 1988. Endotoxin-induced platelet activation in human whole blood in vitro. Thromb. Haemost. 59, 378–382.PubMedGoogle Scholar
  28. Curtis, M.A., Aduse-Opoku, J., Rangarajan, M., 2001. Cysteine Proteases of Porphyromonas gingivalis. Crit. Rev. Oral Biol. Med. 12, 192–216.PubMedCrossRefGoogle Scholar
  29. David, E.H., Jeremy, A.Y., Chris, W., 1998. Molecular basis for structural diversity in the core regions of the lipopolysaccharides of Escherichia coli and Salmonella enterica. Mol. Micro. 30, 221–232.CrossRefGoogle Scholar
  30. Davis, J.P., Chesney, P.J., Wand, P.J., LaVenture, M., 1980. Toxic-shock syndrome: epidemiologic features, recurrence, risk factors, and prevention. N. Engl. J. Med. 303, 1429–1435.PubMedCrossRefGoogle Scholar
  31. de Haas, C., Weeterings, C., Vughs, M., de Groot, P.G., van Strijp, J., Lisman, T., 2009. Staphylococcal superantigen-like 5 activates platelets and supports platelet adhesion under flow conditions, which involves glycoprotein Ibα and αIIbβ3. J. Thromb. Haemostas. 7, 1867–1874.CrossRefGoogle Scholar
  32. Dessing, M.C., Hirst, R.A., de Vos, A.F., van der Poll, T., 2009. Role of Toll-like receptors 2 and 4 in pulmonary inflammation and injury induced by pneumolysin in mice. PLoS One 4, e7993.PubMedCrossRefGoogle Scholar
  33. Fabrice, C., Hind, H.-C., Sandrine, L., Olivier, D., Bruno, P., Archie, M., Olivier, G., 2008. Toll-like receptor 4 ligand can differentially modulate the release of cytokines by human platelets. Br. J. Haematol. 141, 84–91.CrossRefGoogle Scholar
  34. Fitzgerald, J.R., Foster, T.J., Cox, D., 2006. The interaction of bacterial pathogens with platelets. Nat. Rev. Microbiol. 4, 445–457.PubMedCrossRefGoogle Scholar
  35. Fitzpatrick, R.E., Wijeyewickrema, L.C., Pike, R.N., 2009. The gingipains: scissors and glue of the periodontal pathogen, Porphyromonas gingivalis. Future Microbiol. 4, 471–487.PubMedCrossRefGoogle Scholar
  36. Fraser, J., Proft, T., 2008. The bacterial superantigen and superantigen-like proteins. Immunol. Rev. 225, 226–243.PubMedCrossRefGoogle Scholar
  37. García, A., Marini, R.P., Catalfamo, J.L., Knox, K.A., Schauer, D.B., Rogers, A.B., Fox, J.G., 2008. Intravenous Shiga toxin 2 promotes enteritis and renal injury characterized by polymorphonuclear leukocyte infiltration and thrombosis in Dutch Belted rabbits. Microbes Infect. 10, 650–656.PubMedCrossRefGoogle Scholar
  38. Gareau, R., Gruda, J., Micusan, V., 1989. Effect of toxic shock syndrome toxin-1 on human hemostatic parameters. Thromb. Res. 54, 349–356.PubMedCrossRefGoogle Scholar
  39. Ghosh, S., Polanowska-Grabowska, R., Fujii, J., Obrig, T., Gear, A., 2004. Shiga toxin binds to activated platelets. J. Thromb. Haemost. 2, 499–506.PubMedCrossRefGoogle Scholar
  40. Gilbert, R.J., Rossjohn, J., Parker, M.W., Tweten, R.K., Morgan, P.J., Mitchell, T.J., Errington, N., Rowe, A.J., Andrew, P.W., Byron, O., 1998. Self-interaction of pneumolysin, the pore-forming protein toxin of Streptococcus pneumoniae. J. Mol. Biol. 284, 1223–1237.PubMedCrossRefGoogle Scholar
  41. Guessous, F., Marcinkiewicz, M., Polanowska-Grabowska, R., Keepers, T., Obrig, T., Gear, A., 2005a. Shiga toxin 2 and lipopolysaccharide cause monocytic THP-1 cells to release factors which activate platelet function. Thromb. Haemost. 94, 1019–1027.PubMedGoogle Scholar
  42. Guessous, F., Marcinkiewicz, M., Polanowska-Grabowska, R., Kongkhum, S., Heatherly, D., Obrig, T., Gear, A.R.L., 2005b. Shiga Toxin 2 and lipopolysaccharide induce human microvascular endothelial cells to release chemokines and factors that stimulate platelet function. Infect. Immun. 73, 8306–8316.PubMedCrossRefGoogle Scholar
  43. Guo, Y.-L., Liu, D.-Q., Bian, Z., Zhang, C.-Y., Zen, K., 2009. Down-Regulation of platelet surface CD47 expression in Escherichia coli O157:H7 infection-induced thrombocytopenia. PLoS ONE 4, e7131.PubMedCrossRefGoogle Scholar
  44. Hashimoto, K., Jayachandran, M., Owen, W., Miller, V., 2009. Aggregation and microparticle production through Toll-like receptor 4 activation in platelets from recently menopausal women. J. Cardiovasc. Pharmacol. 54, 57–62.PubMedCrossRefGoogle Scholar
  45. Hildebrand, A., Pohl, M., Bhakdi, S., 1991. Staphylococcus aureus alpha-toxin. Dual mechanism of binding to target cells. J. Biol. Chem. 266, 17195–17200.PubMedGoogle Scholar
  46. Houldsworth, S., Andrew, P.W., Mitchell, T.J., 1994. Pneumolysin stimulates production of tumor necrosis factor alpha and interleukin-1 beta by human mononuclear phagocytes. Infect. Immun. 62, 1501–1503.PubMedGoogle Scholar
  47. Hu, H., Peter, K., 2009. Staphylococcal superantigen-like 5 induces platelet activation and thrombosis via binding to GPIbα and GPVI. Circulation 120, S1080.Google Scholar
  48. Ikigai, H., Nakae, T., 1985. Conformational alteration in alpha-toxin from Staphylococcus aureus concomitant with the transformation of the water-soluble monomer to the membrane oligomer. Biochem. Biophys. Res. Commun. 130, 175–181.PubMedCrossRefGoogle Scholar
  49. Ivanov, I.B., Gritsenko, V.A., Kuzmin, M.D., 2006. Staphylococcal secretory inhibitor of platelet microbicidal protein is associated with prostatitis source. J. Med. Microbiol. 55, 1645–1648.PubMedCrossRefGoogle Scholar
  50. Jayachandran, M., Brunn, G.J., Karnicki, K., Miller, R.S., Owen, W.G., Miller, V.M., 2007. In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk. J. Appl. Physiol. 102, 429–433.PubMedCrossRefGoogle Scholar
  51. Johnson, M.K., Boese-Marrazzo, D., Pierce, W.A., 1981. Effects of pneumolysin on human polymorphonuclear leukocytes and platelets. Infect. Immun. 34, 171–176.PubMedGoogle Scholar
  52. Johnson, M.K., Geoffroy, C., Alouf, J.E., 1980. Binding of cholesterol by sulfhydryl-activated cytolysins. Infect. Immun. 27, 97–101.PubMedGoogle Scholar
  53. Kadioglu, A., Coward, W., Colston, M.J., Hewitt, C.R., Andrew, P.W., 2004. CD4-T-lymphocyte interactions with pneumolysin and pneumococci suggest a crucial protective role in the host response to pneumococcal infection. Infect. Immun. 72, 2689–2697.PubMedCrossRefGoogle Scholar
  54. Kanclerski, K., Mollby, R., 1987. Production and purification of Streptococcus pneumoniae hemolysin (pneumolysin). J. Clin. Microbiol. 25, 222–225.PubMedGoogle Scholar
  55. Karpman, D., Papadopoulou, D., Nilsson, K., Sjogren, A.C., Mikaelsson, C., Lethagen, S., 2001. Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome. Blood 97, 3100–3108.PubMedCrossRefGoogle Scholar
  56. Kehoe, M.A., Miller, L., Walker, J.A., Boulnois, G.J., 1987. Nucleotide sequence of the streptolysin O (SLO) gene: structural homologies between SLO and other membrane-damaging, thiol-activated toxins. Infect. Immun. 55, 3228–3232.PubMedGoogle Scholar
  57. Kuckleburg, C., McClenahan, D., Czuprynski, C., 2008a. Platelet activation by Histophilus somni and its lipooligosaccharide induces endothelial cell proinflammatory responses and platelet internalization. Shock 29, 189–196.PubMedGoogle Scholar
  58. Kuckleburg, C., Tiwari, R., Czuprynski, C., 2008b. Endothelial cell apoptosis induced by bacteria-activated platelets requires caspase-8 and -9 and generation of reactive oxygen species. Thromb. Haemost. 99, 363–372.PubMedGoogle Scholar
  59. Kuckleburg, C.J., Sylte, M.J., Inzana, T.J., Corbeil, L.B., Darien, B.J., Czuprynski, C.J., 2005. Bovine platelets activated by Haemophilus somnus and its LOS induce apoptosis in bovine endothelial cells. Microb. Pathogen 38, 23–32.CrossRefGoogle Scholar
  60. Lappin, E., Ferguson, A.J., 2009. Gram-positive toxic shock syndromes. Lancet Infect. Dis. 9, 281–290.PubMedCrossRefGoogle Scholar
  61. Ler, S.G., Lee, F.K., Gopalakrishnakone, P., 2006. Trends in detection of warfare agents: detection methods for ricin, staphylococcal enterotoxin B and T-2 toxin. J. Chromatog. A. 1133, 1–12.CrossRefGoogle Scholar
  62. Lew, D.P., Waldvogel, F.A., 2004. Osteomyelitis. Lancet 364, 369–379.PubMedCrossRefGoogle Scholar
  63. Lindberg, A.A., Brown, J.E., Stramberg, N., Westling-Ryd, M., Schultz, J.E., Karlsson, K.A., 1987. Identification of the carbohydrate receptor for Shiga toxin produced by Shigella dysenteriae type 1. J. Biol. Chem. 262, 1779–1785.PubMedGoogle Scholar
  64. Ling, H., Boodhoo, A., Hazes, B., Cummings, M.D., Armstrong, G.D., Brunton, J.L., Read, R.J., 1998. Structure of the Shiga-like toxin I B-pentamer complexed with an analogue of its receptor Gb3. Biochemistry 37, 1777–1788.PubMedCrossRefGoogle Scholar
  65. Lopez, R., Garcia, E., Garcia, P., Garcia, J.L., 1997. The pneumococcal cell wall degrading enzymes: a modular design to create new lysins? Microb. Drug Resist. 3, 199–211.CrossRefGoogle Scholar
  66. Lourbakos, A., Potempa, J., Travis, J., D’Andrea, M.R., Andrade-Gordon, P., Santulli, R., Mackie, E.J., Pike, R.N., 2001a. Arginine-specific protease from Porphyromonas gingivalis activates protease-activated receptors on human oral epithelial cells and induces interleukin-6 secretion. Infect. Immun. 69, 5121–5130.PubMedCrossRefGoogle Scholar
  67. Lourbakos, A., Yuan, Y., Jenkins, A.L., Travis, J., Andrade-Gordon, P., Santulli, R., Potempa, J., Pike, R.N., 2001b. Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity. Blood 97, 3790–3797.PubMedCrossRefGoogle Scholar
  68. Lowy, F.D., 1998. Staphylococcus aureus infections. N. Engl. J. Med. 339, 520–532.PubMedCrossRefGoogle Scholar
  69. Lynch, J.P., Zhanel, G.G., 2009. Streptococcus pneumoniae: epidemiology, risk factors, and strategies for prevention. Semin. Respir. Crit. Care Med. 30, 189–209.PubMedCrossRefGoogle Scholar
  70. Malley, R., Henneke, P., Morse, S.C., Cieslewicz, M.J., Lipsitch, M., Thompson, C.M., Kurt-Jones, E., Paton, J.C., Wessels, M.R., Golenbock, D.T., 2003. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc. Natl. Acad. Sci. U.S.A. 100, 1966–1971.PubMedCrossRefGoogle Scholar
  71. Manohar, M., Maheswaran, S.K., Frommes, S.P., Lindorfer, R.K., 1967. Platelet damaging factor, a fifth activity of staphylococcal alpha-toxin. J. Bacteriol. 94, 224–231.PubMedGoogle Scholar
  72. Mitchell, T.J., Andrew, P.W., Saunders, F.K., Smith, A.N., Boulnois, G.J., 1991. Complement activation and antibody binding by pneumolysin via a region of the toxin homologous to a human acute-phase protein. Mol. Microbiol. 5, 1883–1888.PubMedCrossRefGoogle Scholar
  73. Montrucchio, G., Bosco, O., Del Sorbo, L., Fascio Pecetto, P., Lupia, E., Goffi, A., Omede, P., Emanuelli, G., Camussi, G., 2003. Mechanisms of the priming effect of low doses of lipopoly-saccharides on leukocyte-dependent platelet aggregation in whole blood. Thromb. Haemost. 90, 872–881.PubMedGoogle Scholar
  74. Morath, S., von Aulock, S., Hartung, T., 2005. Structure/function relationships of lipoteichoic acids. J. Endotoxin. Res. 11, 348–356.PubMedGoogle Scholar
  75. Moreillon, P., Que, Y.A., 2004. Infective endocarditis. Lancet 363, 139–149.PubMedCrossRefGoogle Scholar
  76. Morgan, P.J., Hyman, S.C., Byron, O., Andrew, P.W., Mitchell, T.J., Rowe, A.J., 1994. Modeling the bacterial protein toxin, pneumolysin, in its monomeric and oligomeric form. J. Biol. Chem. 269, 25315–25320.PubMedGoogle Scholar
  77. Morganti, R., Marcondes, S., Baldasso, P., Marangoni, S., De Nucci, G., Antunes, E., 2008. Inhibitory effects of staphylococcal enterotoxin type B on human platelet adhesion in vitro. Platelets 19, 432–439.PubMedCrossRefGoogle Scholar
  78. 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, 1828–1835.PubMedCrossRefGoogle Scholar
  79. Mortara, L.A., Bayer, A.S., 1993. Staphylococcus aureus bacteremia and endocarditis. New diagnostic and therapeutic concepts. Infect. Dis. Clin. North Am. 7, 53–68.PubMedGoogle Scholar
  80. Naito, M., Sakai, E., Shi, Y., Ideguchi, H., Shoji, M., Ohara, N., Yamamoto, K., Nakayama, K., 2006. Porphyromonas gingivalis-induced platelet aggregation in plasma depends on Hgp44 adhesin but not Rgp proteinase. Mol. Micro. 59, 152–167.CrossRefGoogle Scholar
  81. Nylander, M., Lindahl, T.L., Bengtsson, T., Grenegard, M., 2008. The periodontal pathogen Porphyromonas gingivalis sensitises human blood platelets to epinephrine. Platelets 19, 352–358.PubMedCrossRefGoogle Scholar
  82. O’Brien, K.L., Wolfson, L.J., Watt, J.P., Henkle, E., Deloria-Knoll, M., McCall, N., Lee, E., Mulholland, K., Levine, O.S., Cherian, T., 2009. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 374, 893–902.PubMedCrossRefGoogle Scholar
  83. Obrig, T., Moran, T., Brown, J., 1987. The mode of action of Shiga toxin on peptide elongation of eukaryotic protein synthesis. Biochem. J. 244, 287–294.PubMedGoogle Scholar
  84. Palermo, M.S., Exeni, R.A., Fernandez, G.C., 2009. Hemolytic uremic syndrome: pathogenesis and update of interventions. Expert. Rev. Anti-infective Therapy 7, 697–707.CrossRefGoogle Scholar
  85. Paton, J.C., Berry, A.M., Lock, R.A., Hansman, D., Manning, P.A., 1986. Cloning and expression in Escherichia coli of the Streptococcus pneumoniae gene encoding pneumolysin. Infect. Immun. 54, 50–55.PubMedGoogle Scholar
  86. Paton, J.C., Ferrante, A., 1983. Inhibition of human polymorphonuclear leukocyte respiratory burst, bactericidal activity, and migration by pneumolysin. Infect. Immun. 41, 1212–1216.PubMedGoogle Scholar
  87. Paton, J.C., Rowan-Kelly, B., Ferrante, A., 1984. Activation of human complement by the pneumococcal toxin pneumolysin. Infect. Immun. 43, 1085–1087.PubMedGoogle Scholar
  88. Pham, K., Feik, D., Hammond, B.F., Rams, T.E., Whitaker, E.J., 2002. Aggregation of human platelets by gingipain-R from Porphyromonas gingivalis cells and membrane vesicles. Platelets 13, 21–30.PubMedCrossRefGoogle Scholar
  89. Rodgers, G.L., Arguedas, A., Cohen, R., Dagan, R., 2009. Global serotype distribution among Streptococcus pneumoniae isolates causing otitis media in children: potential implications for pneumococcal conjugate vaccines. Vaccine 27, 3802–3810.PubMedCrossRefGoogle Scholar
  90. Satoh, T., Yamashita, Y., Kamiyama, T., Watanabe, J., Steiner, B., Hadváry, P., Arisawa, M., 1993. Tetrafibricin: a nonpeptidic fibrinogen receptor inhibitor from Streptomyces neyagawaensis (I) its GPIIb/IIIa blockage on solid phase binding assay. Thromb. Res. 72, 389–400.PubMedCrossRefGoogle Scholar
  91. Schmitt, C., Meysick, K., O’Brien, A., 1999. Bacterial toxins: friends or foes? Emerg. Infect. Dis. 5, 224–234.Google Scholar
  92. Shah, R., 2009. Protease-activated receptors in cardiovascular health and diseases. Am. Heart J. 157, 253–262.PubMedCrossRefGoogle Scholar
  93. Shannon, O., Hertzen, E., Norrby-Teglund, A., Morgelin, M., Sjobring, U., Bjorck, L., 2007. Severe streptococcal infection is associated with M protein-induced platelet activation and thrombus formation. Mol. Microbiol. 65, 1147–1157.PubMedCrossRefGoogle Scholar
  94. Shashkin, P.N., Brown, G.T., Ghosh, A., Marathe, G.K., McIntyre, T.M., 2008. Lipopolysaccharide is a direct agonist for platelet RNA splicing. J Immunol 181, 3495–3502.PubMedGoogle Scholar
  95. Sheu, J.R., Hsiao, G., Lee, C., Chang, W., Lee, L.W., Su, C.H., Lin, C.H., 2000a. Antiplatelet activity of Staphylococcus aureus lipoteichoic acid is mediated through a cyclic AMP pathway. Thromb. Res. 99, 249–258.PubMedCrossRefGoogle Scholar
  96. Sheu, J.R., Lee, C.R., Lin, C.H., Hsiao, G., Ko, W.C., Chen, Y.C., Yen, M.H., 2000b. Mechanisms involved in the antiplatelet activity of Staphylococcus aureus lipoteichoic acid in human platelets. Thromb. Haemost. 83, 777–784.PubMedGoogle Scholar
  97. Shibazaki, M., Kawabata, Y., Yokochi, T., Nishida, A., Takada, H., Endo, Y., 1999. Complement-dependent accumulation and degradation of platelets in the lung and liver induced by injection of lipopolysaccharides. Infect. Immun. 67, 5186–5191.PubMedGoogle Scholar
  98. Shiraki, R., Inoue, N., Kawasaki, S., Takei, A., Kadotani, M., Ohnishi, Y., Ejiri, J., Kobayashi, S., Hirata, K., Kawashima, S., Yokoyama, M., 2004. Expression of Toll-like receptors on human platelets. Thromb. Res. 113, 379–385.PubMedCrossRefGoogle Scholar
  99. Shoma, S., Tsuchiya, K., Kawamura, I., Nomura, T., Hara, H., Uchiyama, R., Daim, S., Mitsuyama, M., 2008. Critical involvement of pneumolysin in production of interleukin-1α and caspase-1-dependent cytokines in infection with Streptococcus pneumoniae in vitro: a novel function of pneumolysin in caspase-1 activation. Infect. Immun. 76, 1547–1557.PubMedCrossRefGoogle Scholar
  100. Siegel, I., Cohen, S., 1964. Action of staphylococcal toxin on human platelets. J. Infect. Dis. 114, 488–502.PubMedCrossRefGoogle Scholar
  101. Spreer, A., Kerstan, H., Bottcher, T., Gerber, J., Siemer, A., Zysk, G., Mitchell, T.J., Eiffert, H., Nau, R., 2003. Reduced release of pneumolysin by Streptococcus pneumoniae in vitro and in vivo after treatment with nonbacteriolytic antibiotics in comparison to ceftriaxone. Antimicrob. Agents Chemother. 47, 2649–2654.PubMedCrossRefGoogle Scholar
  102. Stahl, A., Sartz, L., Nelsson, A., Bekassy, Z., 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.PubMedCrossRefGoogle Scholar
  103. Stahl, A.-l., Svensson, M., Morgelin, M., Svanborg, C., Tarr, P.I., Mooney, J.C., Watkins, S.L., Johnson, R., Karpman, D., 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.PubMedCrossRefGoogle Scholar
  104. Stevens, D.L., Tanner, M.H., Winship, J., Swarts, R., Ries, K.M., Schlievert, P.M., Kaplan, E., 1989. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N. Engl. J. Med. 321, 1–7.PubMedCrossRefGoogle Scholar
  105. Stockbauer, K.E., Magoun, L., Liu, M., Burns, E.H., Gubba, S., Renish, S., Pan, X., Bodary, S.C., Baker, E., Coburn, J., Leong, J.M., Musser, J.M., 1999. A natural variant of the cysteine protease virulence factor of group A Streptococcus with an arginine-glycine-aspartic acid (RGD) motif preferentially binds human integrins αVβ3 and αIIbβ3. Proc. Natl. Acad. Sci. U.S.A. 96, 242–247.PubMedCrossRefGoogle Scholar
  106. Taylor, F.B., Jr., Bryant, A.E., Blick, K.E., Hack, E., Jansen, P.M., Kosanke, S.D., Stevens, D.L., 1999. Staging of the baboon response to group A streptococci administered intramuscularly: a descriptive study of the clinical symptoms and clinical chemical response patterns. Clin. Infect. Dis. 29, 167–177.PubMedCrossRefGoogle Scholar
  107. te Loo, D., H., L.A., van der Velden, T., Vermeer, M., Preyers, F., Demacker, P., van den Heuvel, L., van Hinsbergh, V., 2000. Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome. Blood 95, 3396–3402.Google Scholar
  108. Thorpe, C.M., Flaumenhaft, R., Hurley, B., Jacewicz, M., Acheson, D.W.K., Keusch, G.T., 1999. Shiga toxins do not directly stimulate alpha-granule secretion or enhance aggregation of human platelets. Acta Haematologica 102, 51–55.PubMedCrossRefGoogle Scholar
  109. Tilley, S.J., Orlova, E.V., Gilbert, R.J., Andrew, P.W., Saibil, H.R., 2005. Structural basis of pore formation by the bacterial toxin pneumolysin. Cell 121, 247–256.PubMedCrossRefGoogle Scholar
  110. Tran, U., Boyle, T., Shupp, J., Hammamieh, R., Jett, M., 2006. Staphylococcal enterotoxin B initiates protein kinase C translocation and eicosanoid metabolism while inhibiting thrombin-induced aggregation in human platelets. Mol. Cell. Biochem. 288, 171–178.PubMedCrossRefGoogle Scholar
  111. Valeva, A., Weisser, A., Walker, B., Kehoe, M., Bayley, H., Bhakdi, S., Palmer, M., 1996. Molecular architecture of a toxin pore: a 15-residue sequence lines the transmembrane channel of staphylococcal alpha-toxin. EMBO J. 15, 1857–1864.PubMedGoogle Scholar
  112. van der Poll, T., Opal, S.M., 2009. Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet 374, 1543–1556.PubMedCrossRefGoogle Scholar
  113. Walker, J.A., Allen, R.L., Falmagne, P., Johnson, M.K., Boulnois, G.J., 1987. Molecular cloning, characterization, and complete nucleotide sequence of the gene for pneumolysin, the sulfhydryl-activated toxin of Streptococcus pneumoniae. Infect. Immun. 55, 1184–1189.PubMedGoogle Scholar
  114. Ward, J.R., Bingle, L., Judge, H.M., Brown, S.B., Storey, R.F., Whyte, M.K., Dower, S.K., Buttle, D.J., Sabroe, I., 2005. Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. Thromb. Haemost. 94, 831–838.PubMedGoogle Scholar
  115. White, J., Rao, G., Gerrard, J., 1974. Effects of the ionophore A23187 on blood platelets I. Influence on aggregation and secretion. Am. J. Pathol. 77, 135–149.PubMedGoogle Scholar
  116. Whitworth, N., Barradas, M., Mikhailidis, D., Dandona, P., 1989. An investigation into the effects of bacterial lipopolysaccharide on human platelets. Eur. J. Haematol. 43, 112–119.PubMedCrossRefGoogle Scholar
  117. Wilson, M., Blum, R., Dandona, P., Mousa, S., 2001. Effects in humans of intravenously administered endotoxin on soluble cell-adhesion molecule and inflammatory markers: a model of human diseases. Clin. Exper. Pharmacol. Physiol. 28, 376–380.CrossRefGoogle Scholar
  118. Yagi, H., Narita, N., Matsumoto, M., Sakurai, Y., Ikari, H., Yoshioka, A., Kita, E., Ikeda, Y., Titani, K., Fujimura, Y., 2001. Enhanced low shear stress induced platelet aggregation by Shiga-like toxin 1 purified from Escherichia coli O157. Am. J. Hematol. 66, 105–115.PubMedCrossRefGoogle Scholar
  119. Yeaman, M., Bayer, A., 2006. Antimicrobial peptides versus invasive infections. Curr. Top. Microbiol. Immunol. 306, 111–152.PubMedCrossRefGoogle Scholar
  120. Yeaman, M.R., Bayer, A.S., Koo, S.P., Foss, W., Sullam, P.M., 1998. Platelet microbicidal proteins and neutrophil defensin disrupt the Staphylococcus aureus cytoplasmic membrane by distinct mechanisms of action. J. Clin. Invest. 101, 178–187.PubMedCrossRefGoogle Scholar
  121. Zähringer, U., Lindner, B., Inamura, S., Heine, H., Alexander, C., 2008. TLR2 – promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity. Immunobiology 213, 205–224.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Molecular and Cellular TherapeuticsRoyal College of Surgeons in IrelandDublinIreland

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