The Biology of Pneumolysin

  • Tim J. Mitchell
  • Catherine E. Dalziel
Part of the Subcellular Biochemistry book series (SCBI, volume 80)


Cholesterol dependent cytolysins are important in the ability of some bacteria to cause disease in man and animals. Pneumolysin (PLY) plays a key role in the diseases caused by Streptococcus pneumoniae (the pneumococcus). This chapter describes the role of PLY in some of the key process in disease. These include induction of cell death by pore formation and toxin-induced apoptosis as well as more subtle effects on gene expression of host cells including epigenetic effects of the toxin. The use of bacterial mutants that either do not express the toxin or express altered versions in biological systems is described. Use of isolated tissue and whole animal systems to dissect the structure/function relationships of the toxin as well as the role played by different activities in the pathogenesis of infection are described. The role of PLY in meningitis and the associated deafness is discussed as well as the role of the toxin in promoting increased lung permeability and inflammation during pneumococcal pneumonia. Different clinical strains of the pneumococcus produce different forms of PLY and the impact of this on disease caused by these strains is discussed. Finally, the impact of this knowledge on the development of treatment and prevention strategies for pneumococcal disease is discussed.


Streptococcuspneumoniae Pneumolysin Pathogenesis of pneumococcal infection Meningitis Human respiratory epithelium Cell death 



Apoptosis-inducing factor


Cholesterol dependent cytolysin


Colony forming units


C-reactive protein


Deubiquitinating enzyme cylindromatosis


Domains 1–3


Human brain microvascular endothelial cells


Intracellular adhesion molecule-1


Membrane attack complex


NOD-like receptor family pyrin domain containing 3


p38 mitogen-activated protein kinase


Plasminogen activator-1




Protein kinase-C




Rho-associated kinase


Site-directed mutagenesis




  1. 1.
    Alcantara RB, Preheim LC, Gentry MJ (1999) Role of pneumolysin’s complement-activating activity during pneumococcal bacteremia in cirrhotic rats. Infect Immun 67:2862–2866PubMedCentralPubMedGoogle Scholar
  2. 2.
    Alcantara RB, Preheim LC, Gentry-Nielsen MJ (2001) Pneumolysin-induced complement depletion during experimental pneumococcal bacteremia. Infect Immun 69:3569–3575PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Alexander JE, Lock RA, Peeters CC, Poolman JT, Andrew PW, Mitchell TJ, Hansman D, Paton JC (1994) Immunization of mice with pneumolysin toxoid confers a significant degree of protection against at least nine serotypes of Streptococcus pneumoniae. Infect Immun 62:5683–5688PubMedCentralPubMedGoogle Scholar
  4. 4.
    Asbell P, Stenson S (1982) Ulcerative keratitis. Survey of 30 years’ laboratory experience. Arch Ophthalmol 100:77–80PubMedCrossRefGoogle Scholar
  5. 5.
    Badwey JA, Curnutte JT, Robinson JM, Berde CB, Karnovsky MJ, Karnovsky ML (1984) Effects of free fatty acids on release of superoxide and on change of shape by human neutrophils. Reversibility by albumin. J Biol Chem 259:7870–7877PubMedGoogle Scholar
  6. 6.
    Balachandran P, Hollingshead SK, Paton JC, Briles DE (2001) The autolytic enzyme LytA of Streptococcus pneumoniae is not responsible for releasing pneumolysin. J Bacteriol 183:3108–3116PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Benton KA, Everson MP, Briles DE (1995) A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice. Infect Immun 63:448–455PubMedCentralPubMedGoogle Scholar
  8. 8.
    Berry AM, Yother J, Briles DE, Hansman D, Paton JC (1989) Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect Immun 57:2037–2042PubMedCentralPubMedGoogle Scholar
  9. 9.
    Beurg M, Hafidi A, Skinner L, Cowan G, Hondarrague Y, Mitchell TJ, Dulon D (2005) The mechanism of pneumolysin-induced cochlear hair cell death in the rat. J Physiol 568:211–227PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Branger J, Knapp S, Weijer S, Leemans JC, Pater JM, Speelman P, Florquin S, van der Poll T (2004) Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice. Infect Immun 72:788–794PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Braun JS, Novak R, Gao G, Murray PJ, Shenep JL (1999) Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide production from macrophages. Infect Immun 67:3750–3756PubMedCentralPubMedGoogle Scholar
  12. 12.
    Braun JS, Sublett JE, Freyer D, Mitchell TJ, Cleveland JL, Tuomanen EI, Weber JR (2002) Pneumococcal pneumolysin and H(2)O(2) mediate brain cell apoptosis during meningitis. J Clin Invest 109:19–27PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Canvin JR, Marvin AP, Sivakumaran M, Paton JC, Boulnois GJ, Andrew PW, Mitchell TJ (1995) The role of pneumolysin and autolysin in the pathology of pneumonia and septicemia in mice infected with a type 2 pneumococcus. J Infect Dis 172:119–123PubMedCrossRefGoogle Scholar
  14. 14.
    Chu J, Thomas LM, Watkins SC, Franchi L, Nunez G, Salter RD (2009) Cholesterol-dependent cytolysins induce rapid release of mature IL-1beta from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner. J Leukoc Biol 86:1227–1238PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Cockeran R, Durandt C, Feldman C, Mitchell TJ, Anderson R (2002) Pneumolysin activates the synthesis and release of interleukin-8 by human neutrophils in vitro. J Infect Dis 186:562–565PubMedCrossRefGoogle Scholar
  16. 16.
    Cockeran R, Steel HC, Mitchell TJ, Feldman C, Anderson R (2001) Pneumolysin potentiates production of prostaglandin E(2) and leukotriene B(4) by human neutrophils. Infect Immun 69:3494–3496PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Cockeran R, Theron AJ, Steel HC, Matlola NM, Mitchell TJ, Feldman C, Anderson R (2001) Proinflammatory interactions of pneumolysin with human neutrophils. J Infect Dis 183:604–611PubMedCrossRefGoogle Scholar
  18. 18.
    Curnutte JT, Badwey JM, Robinson JM, Karnovsky MJ, Karnovsky ML (1984) Studies on the mechanism of superoxide release from human neutrophils stimulated with arachidonate. J Biol Chem 259:11851–11857PubMedGoogle Scholar
  19. 19.
    Dessing MC, Hirst RA, de Vos AF, 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:e7993PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Dockrell DH, Lee M, Lynch DH, Read RC (2001) Immune-mediated phagocytosis and killing of Streptococcus pneumoniae are associated with direct and bystander macrophage apoptosis. J Infect Dis 184:713–722PubMedCrossRefGoogle Scholar
  21. 21.
    Douce G, Ross K, Cowan G, Ma J, Mitchell TJ (2010) Novel mucosal vaccines generated by genetic conjugation of heterologous proteins to pneumolysin (PLY) from Streptococcus pneumoniae. Vaccine 28:3231–3237PubMedCrossRefGoogle Scholar
  22. 22.
    Feldman C, Mitchell TJ, Andrew PW, Boulnois GJ, Read RC, Todd HC, Cole PJ, Wilson R (1990) The effect of Streptococcus pneumoniae pneumolysin on human respiratory epithelium in vitro. Microb Pathog 9:275–284PubMedCrossRefGoogle Scholar
  23. 23.
    Ferrante A, RowanKelly B, Paton JC (1984) Inhibition of in vitro human lymphocyte response by the pneumococcal toxin pneumolysin. Infect Immun 46:585–589PubMedCentralPubMedGoogle Scholar
  24. 24.
    Fortsch C, Hupp S, Ma J, Mitchell TJ, Maier E, Benz R, Iliev AI (2011) Changes in astrocyte shape induced by sublytic concentrations of the cholesterol-dependent cytolysin pneumolysin still require pore-forming capacity. Toxins (Basel) 3:43–62CrossRefGoogle Scholar
  25. 25.
    Giebink GS, Dee TH, Kim Y, Quie PG (1980) Alterations in serum opsonic activity and complement levels in pneumococcal disease. Infect Immun 29:1062–1066PubMedCentralPubMedGoogle Scholar
  26. 26.
    Goulart C, da Silva TR, Rodriguez D, Politano WR, Leite LC, Darrieux M (2013) Characterization of protective immune responses induced by pneumococcal surface protein A in fusion with pneumolysin derivatives. PLoS One 8:e59605PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Hamon MA, Batsche E, Regnault B, Tham TN, Seveau S, Muchardt C, Cossart P (2007) Histone modifications induced by a family of bacterial toxins. Proc Natl Acad Sci USA 104:13467–13472PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Hirst RA, Mohammed BJ, Mitchell TJ, Andrew PW, O’Callaghan C (2004) Streptococcus pneumoniae-induced inhibition of rat ependymal cilia is attenuated by antipneumolysin antibody. Infect Immun 72:6694–6698PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Hirst RA, Yesilkaya H, Clitheroe E, Rutman A, Dufty N, Mitchell TJ, O’Callaghan C, Andrew PW (2002) Sensitivities of human monocytes and epithelial cells to pneumolysin are different. Infect Immun 70:1017–1022PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Hupp S, Fortsch C, Wippel C, Ma J, Mitchell TJ, Iliev AI (2013) Direct transmembrane interaction between actin and the pore-competent, cholesterol-dependent cytolysin pneumolysin. J Mol Biol 425:636–646PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Iliev AI, Djannatian JR, Nau R, Mitchell TJ, Wouters FS (2007) Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin. Proc Natl Acad Sci USA 104:2897–2902PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Iliev AI, Djannatian JR, Opazo F, Gerber J, Nau R, Mitchell TJ, Wouters FS (2009) Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol-dependent, non-lytic and Src-kinase dependent manner inhibits intracellular trafficking. Mol Microbiol 71:461–477PubMedCrossRefGoogle Scholar
  33. 33.
    Jarva H, Jokiranta TS, Wurzner R, Meri S (2003) Complement resistance mechanisms of streptococci. Mol Immunol 40:95–107PubMedCrossRefGoogle Scholar
  34. 34.
    Jefferies JM, Johnston CH, Kirkham LA, Cowan GJ, Ross KS, Smith A, Clarke SC, Brueggemann AB, George RC, Pichon B, Pluschke G, Pfluger V, Mitchell TJ (2007) Presence of nonhemolytic pneumolysin in serotypes of Streptococcus pneumoniae associated with disease outbreaks. J Infect Dis 196:936–944PubMedCrossRefGoogle Scholar
  35. 35.
    Johnson MK, Hobden JA, Hagenah M, OCallaghan RJ, Hill JM, Chen S (1990) The role of pneumolysin in ocular infections with Streptococcus pneumoniae. Curr Eye Res 9:1107–1114Google Scholar
  36. 36.
    Kadioglu A, Gingles NA, Grattan K, Kerr A, Mitchell TJ, Andrew PW (2000) Host cellular immune response to pneumococcal lung infection in mice. Infect Immun 68:492–501PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Kadioglu A, Taylor S, Iannelli F, Pozzi G, Mitchell TJ, Andrew PW (2002) Upper and lower respiratory tract infection by Streptococcus pneumoniae is affected by pneumolysin deficiency and differences in capsule type. Infect Immun 70:2886–2890PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Kamtchoua T, Bologa M, Hopfer R, Neveu D, Hu B, Sheng X, Corde N, Pouzet C, Zimmermann G, Gurunathan S (2013) Safety and immunogenicity of the pneumococcal pneumolysin derivative PlyD1 in a single-antigen protein vaccine candidate in adults. Vaccine 31:327–333PubMedCrossRefGoogle Scholar
  39. 39.
    Kerr AR, Paterson GK, Riboldi-Tunnicliffe A, Mitchell TJ (2005) Innate immune defense against pneumococcal pneumonia requires pulmonary complement component C3. Infect Immun 73:4245–4252PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Kirkham LA, Jefferies JM, Kerr AR, Jing Y, Clarke SC, Smith A, Mitchell TJ (2006) Identification of invasive serotype 1 pneumococcal isolates that express nonhemolytic pneumolysin. J Clin Microbiol 44:151–159PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Kirkham LA, Kerr AR, Douce GR, Paterson GK, Dilts DA, Liu DF, Mitchell TJ (2006) Construction and immunological characterization of a novel nontoxic protective pneumolysin mutant for use in future pneumococcal vaccines. Infect Immun 74:586–593PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Lim JH, Stirling B, Derry J, Koga T, Jono H, Woo CH, Xu H, Bourne P, Ha UH, Ishinaga H, Andalibi A, Feng XH, Zhu H, Huang Y, Zhang W, Weng X, Yan C, Yin Z, Briles DE, Davis RJ, Flavell RA, Li JD (2007) Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections. Immunity 27:349–360PubMedCrossRefGoogle Scholar
  43. 43.
    Lock RA, Zhang QY, Berry AM, Paton JC (1996) Sequence variation in the Streptococcus pneumoniae pneumolysin gene affecting haemolytic activity and electrophoretc mobility of the toxin. Microb Pathogen 21:71–83CrossRefGoogle Scholar
  44. 44.
    Lucas R, Yang G, Gorshkov BA, Zemskov EA, Sridhar S, Umapathy NS, Jezierska-Drutel A, Alieva IB, Leustik M, Hossain H, Fischer B, Catravas JD, Verin AD, Pittet JF, Caldwell RB, Mitchell TJ, Cederbaum SD, Fulton DJ, Matthay MA, Caldwell RW, Romero MJ, Chakraborty T (2012) Protein kinase C-alpha and arginase I mediate pneumolysin-induced pulmonary endothelial hyperpermeability. Am J Respir Cell Mol Biol 47:445–453PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Luttge M, Fulde M, Talay SR, Nerlich A, Rohde M, Preissner KT, Hammerschmidt S, Steinert M, Mitchell TJ, Chhatwal GS, Bergmann S (2012) Streptococcus pneumoniae induces exocytosis of Weibel-Palade bodies in pulmonary endothelial cells. Cell Microbiol 14:210–225PubMedCrossRefGoogle Scholar
  46. 46.
    Lysenko ES, Ratner AJ, Nelson AL, Weiser JN (2005) The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces. PLoS Pathog 1:e1PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT (2003) Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc Natl Acad Sci USA 100:1966–1971PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    McNeela EA, Burke A, Neill DR, Baxter C, Fernandes VE, Ferreira D, Smeaton S, El-Rachkidy R, McLoughlin RM, Mori A, Moran B, Fitzgerald KA, Tschopp J, Petrilli V, Andrew PW, Kadioglu A, Lavelle EC (2010) Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog 6:e1001191PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Mitchell TJ, Andrew PW, Saunders FK, Smith AN, Boulnois GJ (1991) Complement activation and antibody binding by pneumolysin via a region of the toxin homologous to a human acute-phase protein. Mol Microbiol 5:1883–1888PubMedCrossRefGoogle Scholar
  50. 50.
    Moreland JG, Bailey G (2006) Neutrophil transendothelial migration in vitro to Streptococcus pneumoniae is pneumolysin dependent. Am J Physiol Lung Cell Mol Physiol 290:L833–L840PubMedCrossRefGoogle Scholar
  51. 51.
    Norcross EW, Sanders ME, Moore QC 3rd, Marquart ME (2011) Pathogenesis of a clinical ocular strain of Streptococcus pneumoniae and the interaction of pneumolysin with corneal cells. J Bacteriol Parasitol 2:108PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Orihuela CJ, Gao GL, Francis KP, Yu J, Tuomanen EI (2004) Tissue-specific contributions of pneumococcal virulence factors to pathogenesis. J Infect Dis 190(9):1661–1669PubMedCrossRefGoogle Scholar
  53. 53.
    Parker D, Martin FJ, Soong G, Harfenist BS, Aguilar JL, Ratner AJ, Fitzgerald KA, Schindler C, Prince A (2011) Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract. MBio 2:e00016–e00011PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Paton JC, Lock RA, Hansman DJ (1983) Effect of immunization with pneumolysin on survival time of mice challenged with Streptococcus pneumoniae. Infect Immun 40:548–552PubMedCentralPubMedGoogle Scholar
  55. 55.
    Paton JC, Lock RA, Lee CJ, Li JP, Berry AM, Mitchell TJ, Andrew PW, Hansman D, Boulnois GJ (1991) Purification and immunogenicity of genetically obtained pneumolysin toxoids and their conjugation to Streptococcus pneumoniae type 19F polysaccharide. Infect Immun 59:2297–2304PubMedCentralPubMedGoogle Scholar
  56. 56.
    Price KE, Greene NG, Camilli A (2012) Export requirements of pneumolysin in Streptococcus pneumoniae. J Bacteriol 194:3651–3660PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Propst-Graham KL, Preheim LC, Vander Top EA, Snitily MU, Gentry-Nielsen MJ (2007) Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae. BMC Microbiol 7:94Google Scholar
  58. 58.
    Ratner AJ, Aguilar JL, Shchepetov M, Lysenko ES, Weiser JN (2007) Nod1 mediates cytoplasmic sensing of combinations of extracellular bacteria. Cell Microbiol 9:1343–1351PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Ratner AJ, Hippe KR, Aguilar JL, Bender MH, Nelson AL, Weiser JN (2006) Epithelial cells are sensitive detectors of bacterial pore-forming toxins. J Biol Chem 281:12994–12998PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Ratner AJ, Lysenko ES, Paul MN, Weiser JN (2005) Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces. Proc Natl Acad Sci USA 102:3429–3434PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Rayner CF, Jackson AD, Rutman A, Dewar A, Mitchell TJ, Andrew PW, Cole PJ, Wilson R (1995) Interaction of pneumolysin-sufficient and -deficient isogenic variants of Streptococcus pneumoniae with human respiratory mucosa. Infect Immun 63:442–447PubMedCentralPubMedGoogle Scholar
  62. 62.
    Rayner CFJ, Jackson AD, Rutman A, Dewar A, Mitchell TJ, Andrew PW, Cole PJ, Wilson R (1995) Interaction of Pneumolysin-sufficient and -deficient isogenic variants of Streptococcus pneumoniae with human respiratory mucosa. Infect Immun 63:442–447PubMedCentralPubMedGoogle Scholar
  63. 63.
    Ribet D, Hamon M, Gouin E, Nahori MA, Impens F, Neyret-Kahn H, Gevaert K, Vandekerckhove J, Dejean A, Cossart P (2010) Listeria monocytogenes impairs SUMOylation for efficient infection. Nature 464:1192–1195PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Rogers PD, Thornton J, Barker KS, McDaniel DO, Sacks GS, Swiatlo E, McDaniel LS (2003) Pneumolysin-dependent and -independent gene expression identified by cDNA microarray analysis of THP-1 human mononuclear cells stimulated by Streptococcus pneumoniae. Infect Immun 71:2087–2094PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Rossjohn J, Gilbert RJ, Crane D, Morgan PJ, Mitchell TJ, Rowe AJ, Andrew PW, Paton JC, Tweten RK, Parker MW (1998) The molecular mechanism of pneumolysin, a virulence factor from Streptococcus pneumoniae. J Mol Biol 284(2):449–461PubMedCrossRefGoogle Scholar
  66. 66.
    Rubins JB, Charboneau D, Paton JC, Mitchell TJ, Andrew PW, Janoff EN (1995) Dual function of pneumolysin in the early pathogenesis of murine pneumococcal pneumonia. J Clin Invest 95:142–150PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Rubins JB, Duane PG, Charboneau D, Janoff EN (1992) Toxicity of pneumolysin to pulmonary endothelial cells in vitro. Infect Immun 60:1740–1746PubMedCentralPubMedGoogle Scholar
  68. 68.
    Rubins JB, Mitchell TJ, Andrew PW, Niewoehner DE (1994) Pneumolysin activates phospholipase A in pulmonary artery endothelial cells. Infect Immun 62:3829–3836PubMedCentralPubMedGoogle Scholar
  69. 69.
    Rubins JB, Paddock AH, Charboneau D, Berry AM, Paton JC, Janoff EN (1998) Pneumolysin in pneumococcal adherence and colonization. Microb Pathog 25:337–342PubMedCrossRefGoogle Scholar
  70. 70.
    Sanders ME, Norcross EW, Moore QC 3rd, Fratkin J, Thompson H, Marquart ME (2010) Immunization with pneumolysin protects against both retinal and global damage caused by Streptococcus pneumoniae endophthalmitis. J Ocul Pharmacol Ther 26:571–577PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Srivastava A, Henneke P, Visintin A, Morse SC, Martin V, Watkins C, Paton JC, Wessels MR, Golenbock DT, Malley R (2005) The apoptotic response to pneumolysin is Toll-like receptor 4 dependent and protects against pneumococcal disease. Infect Immun 73:6479–6487PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Steinfort C, Wilson R, Mitchell T, Feldman C, Rutman A, Todd H, Sykes D, Walker J, Saunders K, Andrew PW, Boulnois GJ, Cole PJ (1989) Effect of Streptococcus pneumoniae on human respiratory epithelium in vitro. Infect Immun 57:2006–2013PubMedCentralPubMedGoogle Scholar
  73. 73.
    Stringaris AK, Geisenhainer J, Bergmann F, Balshusemann C, Lee U, Zysk G, Mitchell TJ, Keller BU, Kuhnt U, Gerber J, Spreer A, Bahr M, Michel U, Nau R (2002) Neurotoxicity of pneumolysin, a major pneumococcal virulence factor, involves calcium influx and depends on activation of p38 mitogen-activated protein kinase. Neurobiol Dis 11:355–368PubMedCrossRefGoogle Scholar
  74. 74.
    Tilley SJ, Orlova EV, Gilbert RJ, Andrew PW, Saibil HR (2005) Structural basis of pore formation by the bacterial toxin pneumolysin. Cell 121:247–256PubMedCrossRefGoogle Scholar
  75. 75.
    Walker JA, Allen RL, Falmagne P, Johnson MK, Boulnois GJ (1987) Molecular cloning, characterization, and complete nucleotide sequence of the gene for pneumolysin, the sulfhydryl-activated toxin of Streptococcus pneumoniae. Infect Immun 55:1184–1189PubMedCentralPubMedGoogle Scholar
  76. 76.
    Winter AJ, Comis SD, Osborne MP, Tarlow MJ, Stephen J, Andrew PW, Hill J, Mitchell TJ (1997) A role for pneumolysin but not neuraminidase in the hearing loss and cochlear damage induced by experimental pneumococcal meningitis in guinea pigs. Infect Immun 65:4411–4418PubMedCentralPubMedGoogle Scholar
  77. 77.
    Witzenrath M, Gutbier B, Hocke AC, Schmeck B, Hippenstiel S, Berger K, Mitchell TJ, de los Toyos JR, Rosseau S, Suttorp N, Schutte H (2006) Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia. Crit Care Med 34:1947–1954Google Scholar
  78. 78.
    Witzenrath M, Gutbier B, Owen JS, Schmeck B, Mitchell TJ, Mayer K, Thomas MJ, Ishii S, Rosseau S, Suttorp N, Schutte H (2007) Role of platelet-activating factor in pneumolysin-induced acute lung injury. Crit Care Med 35:1756–1762PubMedCrossRefGoogle Scholar
  79. 79.
    Witzenrath M, Pache F, Lorenz D, Koppe U, Gutbier B, Tabeling C, Reppe K, Meixenberger K, Dorhoi A, Ma J, Holmes A, Trendelenburg G, Heimesaat MM, Bereswill S, van der Linden M, Tschopp J, Mitchell TJ, Suttorp N, Opitz B (2011) The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia. J Immunol 187:434–440PubMedCrossRefGoogle Scholar
  80. 80.
    Yuste J, Botto M, Paton JC, Holden DW, Brown JS (2005) Additive inhibition of complement deposition by pneumolysin and PspA facilitates Streptococcus pneumoniae septicemia. J Immunol 175:1813–1819PubMedCrossRefGoogle Scholar
  81. 81.
    Zysk G, Bejo L, Schneider-Wald BK, Nau R, Heinz H (2000) Induction of necrosis and apoptosis of neutrophil granulocytes by Streptococcus pneumoniae. Clin Exp Immunol 122:61–66PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Zysk G, Schneider-Wald BK, Hwang JH, Bejo L, Kim KS, Mitchell TJ, Hakenbeck R, Heinz HP (2001) Pneumolysin is the main inducer of cytotoxicity to brain microvascular endothelial cells caused by Streptococcus pneumoniae. Infect Immun 69:845–852PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Institute of Microbiology and InfectionUniversity of BirminghamBirminghamUK
  2. 2.School of Immunity and Infection, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
  3. 3.Institute of Infection, Immunity and InflammationUniversity of GlasgowGlasgowUK

Personalised recommendations