Summary: Exotoxins produced by certain strains of streptococci, particularly those of group A (STREPTOCOCCUS PYOGENES), that cause HEMOLYSIS.

Top Publications

  1. Holmlund E, Quiambao B, Ollgren J, Nohynek H, Kayhty H. Development of natural antibodies to pneumococcal surface protein A, pneumococcal surface adhesin A and pneumolysin in Filipino pregnant women and their infants in relation to pneumococcal carriage. Vaccine. 2006;24:57-65 pubmed
    ..78, 0.61-0.99). This indicates that high maternal anti-Ply could be associated with lower pneumococcal carriage acquisition in infants. ..
  2. DeNoel P, Philipp M, Doyle L, Martin D, Carletti G, Poolman J. A protein-based pneumococcal vaccine protects rhesus macaques from pneumonia after experimental infection with Streptococcus pneumoniae. Vaccine. 2011;29:5495-501 pubmed publisher
    ..In conclusion, AS02-adjuvanted PhtD-dPly vaccine protects against S. pneumoniae-induced pneumonia. It is probable that the protection is at least partially mediated by PhtD- and Ply-specific antibodies. ..
  3. Price K, Camilli A. Pneumolysin localizes to the cell wall of Streptococcus pneumoniae. J Bacteriol. 2009;191:2163-8 pubmed publisher
    ..Hemolytic assays revealed that this cell wall-localized Ply is active. Additionally, cell wall-localized Ply is accessible to extracellular protease and is detergent releasable. ..
  4. Propst Graham K, Preheim L, Vander Top E, Snitily M, Gentry Nielsen M. Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae. BMC Microbiol. 2007;7:94 pubmed
    ..They also suggest that pneumolysin may be a particularly potent pneumococcal virulence factor in the setting of cirrhosis. ..
  5. Förtsch C, Hupp S, Ma J, Mitchell T, Maier E, Benz R, et al. Changes in astrocyte shape induced by sublytic concentrations of the cholesterol-dependent cytolysin pneumolysin still require pore-forming capacity. Toxins (Basel). 2011;3:43-62 pubmed publisher
  6. Munoz Almagro C, Gala S, Selva L, Jordan I, Tarrago D, Pallares R. DNA bacterial load in children and adolescents with pneumococcal pneumonia and empyema. Eur J Clin Microbiol Infect Dis. 2011;30:327-35 pubmed publisher
    ..001). Quantification of pneumococcal DBL by real-time PCR may be helpful for the diagnosis and clinical management of pediatric patients with pneumonia and empyema...
  7. Tai S. Streptococcus pneumoniae protein vaccine candidates: properties, activities and animal studies. Crit Rev Microbiol. 2006;32:139-53 pubmed
    ..This communication provides a review on the biochemical properties of these protein candidates, their immunization results in animal studies, and perspectives on the development of protein-based pneumococcal vaccine. ..
  8. Malley R, Henneke P, Morse S, Cieslewicz M, Lipsitch M, Thompson C, et al. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc Natl Acad Sci U S A. 2003;100:1966-71 pubmed
    ..We conclude that the interaction of pneumolysin with TLR4 is critically involved in the innate immune response to pneumococcus. ..
  9. Hakansson A, Bentley C, Shakhnovic E, Wessels M. Cytolysin-dependent evasion of lysosomal killing. Proc Natl Acad Sci U S A. 2005;102:5192-7 pubmed

More Information


  1. Rijneveld A, van den Dobbelsteen G, Florquin S, Standiford T, Speelman P, van Alphen L, et al. Roles of interleukin-6 and macrophage inflammatory protein-2 in pneumolysin-induced lung inflammation in mice. J Infect Dis. 2002;185:123-6 pubmed
    ..PLY may play an important role in the induction of an inflammatory response in the pulmonary compartment in the early phase of pneumococcal pneumonia. ..
  2. Harder J, Franchi L, Muñoz Planillo R, Park J, Reimer T, Nunez G. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. J Immunol. 2009;183:5823-9 pubmed publisher
    ..pyogenes peritoneal infection. These results indicate that caspase-1 activation in response to S. pyogenes infection requires NF-kappaB and the virulence factor streptolysin O, but proceeds independently of P2X7R and TLR signaling. ..
  3. Miyoshi Akiyama T, Takamatsu D, Koyanagi M, Zhao J, Imanishi K, Uchiyama T. Cytocidal effect of Streptococcus pyogenes on mouse neutrophils in vivo and the critical role of streptolysin S. J Infect Dis. 2005;192:107-16 pubmed
    ..Our findings suggest that, in addition to the production of antiphagocytic factors and survival inside phagocytes, GAS uses a more aggressive method--the elimination of neutrophils--to evade the host's innate immune system. ..
  4. Tilley S, Orlova E, Gilbert R, Andrew P, Saibil H. Structural basis of pore formation by the bacterial toxin pneumolysin. Cell. 2005;121:247-56 pubmed
    ..With an oligomer size of up to 44 subunits in the pore, this assembly creates a transmembrane channel 260 A in diameter lined by 176 beta strands. ..
  5. Corrotte M, Fernandes M, Tam C, Andrews N. Toxin pores endocytosed during plasma membrane repair traffic into the lumen of MVBs for degradation. Traffic. 2012;13:483-94 pubmed publisher
    ..Thus, cells dispose of SLO transmembrane pores by ubiquitination/ESCRT-dependent sorting into the lumen of late endosomes/lysosomes. ..
  6. Salha D, Szeto J, Myers L, Claus C, Sheung A, Tang M, et al. Neutralizing antibodies elicited by a novel detoxified pneumolysin derivative, PlyD1, provide protection against both pneumococcal infection and lung injury. Infect Immun. 2012;80:2212-20 pubmed publisher
    ..Our detoxified PlyD1 antigen elicits such PLY neutralizing antibodies, thus serving as a candidate vaccine antigen for the prevention of pneumococcal pneumonia. ..
  7. Bernatoniene J, Zhang Q, Dogan S, Mitchell T, Paton J, Finn A. Induction of CC and CXC chemokines in human antigen-presenting dendritic cells by the pneumococcal proteins pneumolysin and CbpA, and the role played by toll-like receptor 4, NF-kappaB, and mitogen-activated protein kinases. J Infect Dis. 2008;198:1823-33 pubmed publisher
    ..Inhibition of NF-kappaB and several mitogen-activated protein kinase signaling pathways also reduced chemokine release. Chemokine induction in DCs by CbpA and Ply may be important for their potential use in future pneumococcal vaccines. ..
  8. Kirkham L, Kerr A, Douce G, Paterson G, Dilts D, Liu D, et al. Construction and immunological characterization of a novel nontoxic protective pneumolysin mutant for use in future pneumococcal vaccines. Infect Immun. 2006;74:586-93 pubmed
    ..Vaccination with this mutant protects mice from challenge with S. pneumoniae. Incorporation of this mutant pneumolysin into current pneumococcal vaccines may increase their efficacy. ..
  9. Feldman C, Anderson R, Cockeran R, Mitchell T, Cole P, Wilson R. The effects of pneumolysin and hydrogen peroxide, alone and in combination, on human ciliated epithelium in vitro. Respir Med. 2002;96:580-5 pubmed
    ..These actions of pneumolysin and H2O2 may contribute to the pathogenesis of respiratory tract infections caused by the pneumococcus. ..
  10. Thornton J, McDaniel L. THP-1 monocytes up-regulate intercellular adhesion molecule 1 in response to pneumolysin from Streptococcus pneumoniae. Infect Immun. 2005;73:6493-8 pubmed
    ..These data indicate that PLY induces transcription and production of a cell adhesion molecule involved in the inflammatory response that may play a role in pneumococcal infection. ..
  11. Price K, Greene N, Camilli A. Export requirements of pneumolysin in Streptococcus pneumoniae. J Bacteriol. 2012;194:3651-60 pubmed publisher
    ..We show that B. subtilis can export Ply, suggesting that the export pathway is conserved. Finally, through truncation and domain swapping analyses, we show that export is dependent on domain 2 of Ply. ..
  12. Heuck A, Tweten R, Johnson A. Assembly and topography of the prepore complex in cholesterol-dependent cytolysins. J Biol Chem. 2003;278:31218-25 pubmed
  13. Garcia Suarez M, Cima Cabal M, Flórez N, Garcia P, Cernuda Cernuda R, Astudillo A, et al. Protection against pneumococcal pneumonia in mice by monoclonal antibodies to pneumolysin. Infect Immun. 2004;72:4534-40 pubmed
    ..Furthermore, MAb administration was associated with a significant decrease in bacterial lung colonization and lower frequencies of bacteremia and tissue injury with respect to the results for the control groups. ..
  14. Michos A, Gryllos I, Hakansson A, Srivastava A, Kokkotou E, Wessels M. Enhancement of streptolysin O activity and intrinsic cytotoxic effects of the group A streptococcal toxin, NAD-glycohydrolase. J Biol Chem. 2006;281:8216-23 pubmed
    ..Together, the results have provided mechanistic insight into the cytotoxic effects of a unique bipartite bacterial toxin. ..
  15. Mitchell D, Lee S, Pence M, Markley A, Limm J, Nizet V, et al. Structural and functional dissection of the heterocyclic peptide cytotoxin streptolysin S. J Biol Chem. 2009;284:13004-12 pubmed publisher
    ..This new structural information has ramifications for future antimicrobial therapies. ..
  16. Logsdon L, Hakansson A, Cortés G, Wessels M. Streptolysin O inhibits clathrin-dependent internalization of group A Streptococcus. MBio. 2011;2:e00332-10 pubmed publisher
    ..We conclude that SLO interferes with the internalization of GAS through local perturbation of the keratinocyte cell membrane and disruption of a clathrin-dependent uptake pathway. ..
  17. Dogan S, Zhang Q, Pridmore A, Mitchell T, Finn A, Murdoch C. Pneumolysin-induced CXCL8 production by nasopharyngeal epithelial cells is dependent on calcium flux and MAPK activation via Toll-like receptor 4. Microbes Infect. 2011;13:65-75 pubmed publisher
    ..This may be important in regulating nasopharyngeal immunity against pneumococcal colonization. ..
  18. Sonnen A, Rowe A, Andrew P, Gilbert R. Oligomerisation of pneumolysin on cholesterol crystals: similarities to the behaviour of polyene antibiotics. Toxicon. 2008;51:1554-9 pubmed publisher
    ..Here we provide further insights into the pneumolysin oligomer by studying the interaction of pneumolysin with cholesterol crystals, comparing the results to those obtained for polyene antibiotics, which also bind cholesterol. ..
  19. Lizcano A, Chin T, Sauer K, Tuomanen E, Orihuela C. Early biofilm formation on microtiter plates is not correlated with the invasive disease potential of Streptococcus pneumoniae. Microb Pathog. 2010;48:124-30 pubmed publisher
    ..In summary, these studies suggest that the ability to form early biofilms in vitro does not reflect virulence potential. More complex studies are required to determine if biofilm formation is important for virulence. ..
  20. Husmann M, Dersch K, Bobkiewicz W, Beckmann E, Veerachato G, Bhakdi S. Differential role of p38 mitogen activated protein kinase for cellular recovery from attack by pore-forming S. aureus alpha-toxin or streptolysin O. Biochem Biophys Res Commun. 2006;344:1128-34 pubmed
    ..In contrast, blockade of p38 in SLO permeabilized cells did not affect the capacity of the cells to replenish their ATP stores. ..
  21. Stringaris A, Geisenhainer J, Bergmann F, Balshüsemann C, Lee U, Zysk G, et al. Neurotoxicity of pneumolysin, a major pneumococcal virulence factor, involves calcium influx and depends on activation of p38 mitogen-activated protein kinase. Neurobiol Dis. 2002;11:355-68 pubmed
    ..Modulation of cell death pathways activated by pneumolysin may influence the outcome of pneumococcal meningitis. ..
  22. Sakurai A, Maruyama F, Funao J, Nozawa T, Aikawa C, Okahashi N, et al. Specific behavior of intracellular Streptococcus pyogenes that has undergone autophagic degradation is associated with bacterial streptolysin O and host small G proteins Rab5 and Rab7. J Biol Chem. 2010;285:22666-75 pubmed publisher
    ..This intracellular behavior of GAS is unique and distinct from that of other types of bacterial invaders. Our results provide a new picture of GAS infection and host-cell responses in epithelial cells. ..
  23. El Rachkidy R, Davies N, Andrew P. Pneumolysin generates multiple conductance pores in the membrane of nucleated cells. Biochem Biophys Res Commun. 2008;368:786-92 pubmed publisher
    ..The WT toxin also induced channels when given to the inside surface of the plasma membrane. ..
  24. Hupp S, Heimeroth V, Wippel C, Förtsch C, Ma J, Mitchell T, et al. Astrocytic tissue remodeling by the meningitis neurotoxin pneumolysin facilitates pathogen tissue penetration and produces interstitial brain edema. Glia. 2012;60:137-46 pubmed publisher
    ..We suggest that PLY can increase the permeability of brain tissue toward pathogenic factors and bacteria in the course of meningitis, thus contributing to the deterioration caused by the disease. ..
  25. Douce G, Ross K, Cowan G, Ma J, Mitchell T. Novel mucosal vaccines generated by genetic conjugation of heterologous proteins to pneumolysin (PLY) from Streptococcus pneumoniae. Vaccine. 2010;28:3231-7 pubmed publisher
  26. Babiychuk E, Monastyrskaya K, Potez S, Draeger A. Intracellular Ca(2+) operates a switch between repair and lysis of streptolysin O-perforated cells. Cell Death Differ. 2009;16:1126-34 pubmed publisher
    ..These findings show that the extent of [Ca(2+)](i) elevation determines the fate of targeted cells and establishes how different Ca(2+)-dependent mechanisms facilitate either cell survival or death. ..
  27. Jefferies J, Johnston C, Kirkham L, Cowan G, Ross K, Smith A, et al. Presence of nonhemolytic pneumolysin in serotypes of Streptococcus pneumoniae associated with disease outbreaks. J Infect Dis. 2007;196:936-44 pubmed
    ..Serotype 1 and 8 pneumococci are known to be associated with outbreaks of invasive disease. The nonhemolytic pneumolysin allele is therefore associated with the dominant clones of outbreak-associated serotypes of S. pneumoniae. ..
  28. Lim J, Stirling B, Derry J, Koga T, Jono H, Woo C, et al. Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections. Immunity. 2007;27:349-60 pubmed
    ..Thus, CYLD is detrimental for host survival, thereby indicating a mechanism underlying the high early mortality of pneumococcal pneumonia. ..
  29. Sekiya K, Akagi T, Tatsuta K, Sakakura E, Hashikawa T, Abe A, et al. Ultrastructural analysis of the membrane insertion of domain 3 of streptolysin O. Microbes Infect. 2007;9:1341-50 pubmed
    ..On the basis of a model of the oligomeric structure of SLO, we propose some new details of the mechanism of hemolysis by SLO. ..
  30. Koga T, Lim J, Jono H, Ha U, Xu H, Ishinaga H, et al. Tumor suppressor cylindromatosis acts as a negative regulator for Streptococcus pneumoniae-induced NFAT signaling. J Biol Chem. 2008;283:12546-54 pubmed publisher
    ..pneumoniae infections through the NFAT-dependent mechanism and further identify CYLD as a negative regulator for NFAT signaling, thereby opening up new therapeutic targets for these diseases. ..
  31. Schmeck B, Huber S, Moog K, Zahlten J, Hocke A, Opitz B, et al. Pneumococci induced TLR- and Rac1-dependent NF-kappaB-recruitment to the IL-8 promoter in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2006;290:L730-L737 pubmed
    ..In summary, these results suggest that S. pneumoniae activate human epithelial cells by TLR1/2 and a phosphatidylinositol 3-kinase- and Rac1-dependent NF-kappaB-recruitment to the IL-8 promoter. ..
  32. Hupp S, Förtsch C, Wippel C, Ma J, Mitchell T, Iliev A. Direct transmembrane interaction between actin and the pore-competent, cholesterol-dependent cytolysin pneumolysin. J Mol Biol. 2013;425:636-46 pubmed publisher
    ..Our results demonstrate the first example of a direct interaction of a pore-forming toxin with cytoskeletal components, suggesting that the cross talk between pore-forming cytolysins and cells is more complex than previously thought. ..
  33. Lim J, Park S, Bong S, Chi Y, Lee K. Characterization of pneumolysin from Streptococcus pneumoniae, interacting with carbohydrate moiety and cholesterol as a component of cell membrane. Biochem Biophys Res Commun. 2013;430:659-63 pubmed publisher
  34. Bricker A, Cywes C, Ashbaugh C, Wessels M. NAD+-glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci. Mol Microbiol. 2002;44:257-69 pubmed
    ..We conclude that NAD+-glycohydrolase is a novel type of bacterial toxin that acts intracellularly in the infected host to enhance the survival and proliferation of an extracellular pathogen. ..
  35. Kadioglu A, Taylor S, Iannelli F, Pozzi G, Mitchell T, Andrew P. Upper and lower respiratory tract infection by Streptococcus pneumoniae is affected by pneumolysin deficiency and differences in capsule type. Infect Immun. 2002;70:2886-90 pubmed
    ..The combination of capsule type and genetic background also determined virulence. Thus, the wild-type serotype 3 strain was virulent, whereas the capsule-switched mutant was avirulent. ..
  36. Zhang Q, Choo S, Finn A. Immune responses to novel pneumococcal proteins pneumolysin, PspA, PsaA, and CbpA in adenoidal B cells from children. Infect Immun. 2002;70:5363-9 pubmed
    ..Some protein antigens may also prime for mucosal IgA memory. These data support the effort to explore mucosal immunization against pneumococcal infection. ..
  37. Fuller J, Camus A, Duncan C, Nizet V, Bast D, Thune R, et al. Identification of a streptolysin S-associated gene cluster and its role in the pathogenesis of Streptococcus iniae disease. Infect Immun. 2002;70:5730-9 pubmed
    ..These studies demonstrated that S. iniae SLS expression is required for local tissue necrosis but does not contribute to the establishment of bacteremia or to resistance to phagocytic clearance. ..
  38. Ng E, Costa J, Samiy N, Ruoff K, Connolly E, Cousins F, et al. Contribution of pneumolysin and autolysin to the pathogenesis of experimental pneumococcal endophthalmitis. Retina. 2002;22:622-32 pubmed
    ..pneumoniae. Autolysin-deficient S. pneumoniae shows a similar degree of attenuated virulence. Pneumolysin and autolysin may contribute to the early pathogenesis of pneumococcal endophthalmitis. ..
  39. Lucas R, Yang G, Gorshkov B, Zemskov E, Sridhar S, Umapathy N, et al. Protein kinase C-? and arginase I mediate pneumolysin-induced pulmonary endothelial hyperpermeability. Am J Respir Cell Mol Biol. 2012;47:445-53 pubmed publisher
    ..These results identify PKC-? and arginase I as potential upstream and downstream therapeutic targets in PLY-induced pulmonary endothelial dysfunction. ..
  40. Nizet V. Streptococcal beta-hemolysins: genetics and role in disease pathogenesis. Trends Microbiol. 2002;10:575-80 pubmed
    ..The generation of isogenic GAS and GBS beta-hemolysin-deficient mutants and their analysis using in vitro and in vivo model systems has shown that both toxins function as virulence factors in the pathogenesis of invasive infections. ..
  41. Colino J, Snapper C. Two distinct mechanisms for induction of dendritic cell apoptosis in response to intact Streptococcus pneumoniae. J Immunol. 2003;171:2354-65 pubmed
    ..These data are the first to define two mechanistically distinct pathways of DC apoptosis induction in response to an extracellular bacterium that likely have important consequences for the establishment of antibacterial immunity. ..
  42. Lucas R, Sridhar S, Rick F, Gorshkov B, Umapathy N, Yang G, et al. Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema. Proc Natl Acad Sci U S A. 2012;109:2084-9 pubmed publisher
    ..These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema. ..
  43. Orihuela C, Gao G, Francis K, Yu J, Tuomanen E. Tissue-specific contributions of pneumococcal virulence factors to pathogenesis. J Infect Dis. 2004;190:1661-9 pubmed
    ..We conclude that transitions between body sites require virulence determinants distinct from those involved in organ-specific replication...
  44. Hirst R, Kadioglu A, O Callaghan C, Andrew P. The role of pneumolysin in pneumococcal pneumonia and meningitis. Clin Exp Immunol. 2004;138:195-201 pubmed
    ..One of the main toxins released from pneumococci is the membrane pore forming toxin pneumolysin. Here we review the extensive studies on the role of pneumolysin in the pathogenesis of pneumococcal diseases. ..
  45. Srivastava A, Henneke P, Visintin A, Morse S, Martin V, Watkins C, et al. The apoptotic response to pneumolysin is Toll-like receptor 4 dependent and protects against pneumococcal disease. Infect Immun. 2005;73:6479-87 pubmed
    ..Overall, our results strongly suggest that protection against pneumococcal disease is dependent on the TLR4-mediated enhancement of pneumolysin-induced apoptosis. ..
  46. Cruse G, Fernandes V, de Salort J, Pankhania D, Marinas M, Brewin H, et al. Human lung mast cells mediate pneumococcal cell death in response to activation by pneumolysin. J Immunol. 2010;184:7108-15 pubmed publisher
    ..This suggests that mast cells provide an early warning system and potentially limit pneumococcal dissemination early in the course of invasive pulmonary pneumococcal disease. ..
  47. McNeela E, Burke A, Neill D, Baxter C, Fernandes V, Ferreira D, et al. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog. 2010;6:e1001191 pubmed publisher
    ..Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumoniae. These results add significantly to our understanding of the interactions between PLY and the immune system. ..
  48. Ato M, Ikebe T, Kawabata H, Takemori T, Watanabe H. Incompetence of neutrophils to invasive group A streptococcus is attributed to induction of plural virulence factors by dysfunction of a regulator. PLoS ONE. 2008;3:e3455 pubmed publisher
    ..These results suggest that the abilities of GAS to abrogate PMN functions can determine the onset and severity of invasive GAS infection. ..
  49. Magassa N, Chandrasekaran S, Caparon M. Streptococcus pyogenes cytolysin-mediated translocation does not require pore formation by streptolysin O. EMBO Rep. 2010;11:400-5 pubmed publisher
    ..Moreover, despite the ability of mutants to translocate SPN, their cytotoxic effect requires SLO pore formation. ..
  50. Lee S, Mitchell D, Markley A, Hensler M, Gonzalez D, Wohlrab A, et al. Discovery of a widely distributed toxin biosynthetic gene cluster. Proc Natl Acad Sci U S A. 2008;105:5879-84 pubmed publisher
    ..Given our findings, it is likely that the discovery of similar peptidic toxins will rapidly expand to existing and emerging genomes. ..
  51. Walev I, Hombach M, Bobkiewicz W, Fenske D, Bhakdi S, Husmann M. Resealing of large transmembrane pores produced by streptolysin O in nucleated cells is accompanied by NF-kappaB activation and downstream events. FASEB J. 2002;16:237-9 pubmed
    ..The study provides definitive evidence that a transient transmembrane pore suffices to trigger productive transcriptional activation in a target cell. ..
  52. Kadioglu A, Coward W, Colston M, Hewitt C, Andrew P. CD4-T-lymphocyte interactions with pneumolysin and pneumococci suggest a crucial protective role in the host response to pneumococcal infection. Infect Immun. 2004;72:2689-97 pubmed
    ..There is evidence that the activation of IL-4 expression occurs during migration. ..
  53. Kano F, Kondo H, Yamamoto A, Tanaka A, Hosokawa N, Nagata K, et al. The maintenance of the endoplasmic reticulum network is regulated by p47, a cofactor of p97, through phosphorylation by cdc2 kinase. Genes Cells. 2005;10:333-44 pubmed
  54. Datta V, Myskowski S, Kwinn L, Chiem D, Varki N, Kansal R, et al. Mutational analysis of the group A streptococcal operon encoding streptolysin S and its virulence role in invasive infection. Mol Microbiol. 2005;56:681-95 pubmed
    ..We conclude that all genetic components of the sag operon are required for expression of functional SLS, an important virulence factor in the pathogenesis of invasive M1T1 GAS infection. ..
  55. Ferreira D, Arêas A, Darrieux M, Leite L, Miyaji E. DNA vaccines based on genetically detoxified derivatives of pneumolysin fail to protect mice against challenge with Streptococcus pneumoniae. FEMS Immunol Med Microbiol. 2006;46:291-7 pubmed
    ..Immunization with DNA vaccines expressing pneumolysoids, on the other hand, induced a significantly lower antibody response and no protection was observed. ..
  56. Maus U, Srivastava M, Paton J, Mack M, Everhart M, Blackwell T, et al. Pneumolysin-induced lung injury is independent of leukocyte trafficking into the alveolar space. J Immunol. 2004;173:1307-12 pubmed
    ..These data indicate that PLY-induced lung injury results from direct pneumotoxic effects on the alveolar-capillary barrier and is independent of both resident and recruited phagocytic cells. ..
  57. Laine C, Mwangi T, Thompson C, Obiero J, Lipsitch M, Scott J. Age-specific immunoglobulin g (IgG) and IgA to pneumococcal protein antigens in a population in coastal kenya. Infect Immun. 2004;72:3331-5 pubmed
    ..001). No decline was observed in the sera of the elderly. Anti-protein IgG concentrations were only weakly correlated (0.30 < r < 0.56; P < 0.0001), as were IgA concentrations (0.24 < r < 0.54; P < 0.0001). ..
  58. Braun J, Hoffmann O, Schickhaus M, Freyer D, Dagand E, Bermpohl D, et al. Pneumolysin causes neuronal cell death through mitochondrial damage. Infect Immun. 2007;75:4245-54 pubmed
    ..Considering this, blocking of pneumolysin may be a promising cytoprotective strategy in pneumococcal meningitis and other infections. ..
  59. Locke J, Colvin K, Varki N, Vicknair M, Nizet V, Buchanan J. Streptococcus iniae beta-hemolysin streptolysin S is a virulence factor in fish infection. Dis Aquat Organ. 2007;76:17-26 pubmed
    ..The neutralization of SLS could represent a novel strategy for control of S. iniae infection in aquaculture. ..
  60. Fontaine M, Lee J, Kehoe M. Combined contributions of streptolysin O and streptolysin S to virulence of serotype M5 Streptococcus pyogenes strain Manfredo. Infect Immun. 2003;71:3857-65 pubmed
  61. Humar D, Datta V, Bast D, Beall B, de Azavedo J, Nizet V. Streptolysin S and necrotising infections produced by group G streptococcus. Lancet. 2002;359:124-9 pubmed
    ..SLS expression contributes to the pathogenesis of streptococcal necrotising soft tissue infection. ..
  62. Idone V, Tam C, Goss J, Toomre D, Pypaert M, Andrews N. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. J Cell Biol. 2008;180:905-14 pubmed publisher
    ..These findings provide an important new insight into how cells protect themselves not only from mechanical injury but also from microbial toxins and pore-forming proteins produced by the immune system. ..
  63. Stassen M, Muller C, Richter C, Neudörfl C, Hültner L, Bhakdi S, et al. The streptococcal exotoxin streptolysin O activates mast cells to produce tumor necrosis factor alpha by p38 mitogen-activated protein kinase- and protein kinase C-dependent pathways. Infect Immun. 2003;71:6171-7 pubmed
    ..However, hyperstimulation of mast cells might also lead to overproduction of TNF-alpha, which would then promote the development of toxic streptococcal syndromes. ..
  64. Ogunniyi A, Woodrow M, Poolman J, Paton J. Protection against Streptococcus pneumoniae elicited by immunization with pneumolysin and CbpA. Infect Immun. 2001;69:5997-6003 pubmed
    ..Mice immunized with PdB in MPL plus AlPO4 were also significantly better protected than mice that received PdB in AlPO4 alone. ..
  65. Koppe U, Högner K, Doehn J, Müller H, Witzenrath M, Gutbier B, et al. Streptococcus pneumoniae stimulates a STING- and IFN regulatory factor 3-dependent type I IFN production in macrophages, which regulates RANTES production in macrophages, cocultured alveolar epithelial cells, and mouse lungs. J Immunol. 2012;188:811-7 pubmed publisher
    ..In conclusion, we identified an immune sensing pathway detecting S. pneumoniae that triggers a type I IFN response and positively regulates RANTES production. ..
  66. Jounblat R, Kadioglu A, Mitchell T, Andrew P. Pneumococcal behavior and host responses during bronchopneumonia are affected differently by the cytolytic and complement-activating activities of pneumolysin. Infect Immun. 2003;71:1813-9 pubmed
    ..The complement-activating activity of pneumolysin affected the accumulation of T cells, whereas the toxin's cytolytic activity influenced neutrophil recruitment into lung tissue. ..
  67. Sierig G, Cywes C, Wessels M, Ashbaugh C. Cytotoxic effects of streptolysin o and streptolysin s enhance the virulence of poorly encapsulated group a streptococci. Infect Immun. 2003;71:446-55 pubmed
    ..Compared to SLO, SLS in this strain background has a more modest influence on GAS pathogenicity and the effect does not appear to involve bacterial resistance to phagocytosis. ..
  68. Vidal J, Ludewick H, Kunkel R, Zahner D, Klugman K. The LuxS-dependent quorum-sensing system regulates early biofilm formation by Streptococcus pneumoniae strain D39. Infect Immun. 2011;79:4050-60 pubmed publisher
    ..In conclusion, the luxS-controlled QS system is a key regulator of early biofilm formation by S. pneumoniae strain D39. ..
  69. Harvey R, Ogunniyi A, Chen A, Paton J. Pneumolysin with low hemolytic activity confers an early growth advantage to Streptococcus pneumoniae in the blood. Infect Immun. 2011;79:4122-30 pubmed publisher
    ..In summary, we show that low-hemolytic-activity Ply alleles contribute to systemic virulence and may provide a survival advantage in the blood. Moreover, pneumococci expressing such alleles remain vulnerable to Ply-based vaccines. ..
  70. Witzenrath M, Pache F, Lorenz D, Koppe U, Gutbier B, Tabeling C, et al. The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia. J Immunol. 2011;187:434-40 pubmed publisher
    ..The study indicates that a virulence factor polymorphism may substantially affect the recognition of bacteria by the innate immune system. ..
  71. Kimoto H, Fujii Y, Hirano S, Yokota Y, Taketo A. Genetic and biochemical properties of streptococcal NAD-glycohydrolase inhibitor. J Biol Chem. 2006;281:9181-9 pubmed
    ..Unlike other bacterial NADase inhibitors, SNI was thermostable. This protein, coexpressed and complexed with NADase, may protect the producer cocci from exhaustion of NAD. ..
  72. Feldman C, Cockeran R, Jedrzejas M, Mitchell T, Anderson R. Hyaluronidase augments pneumolysin-mediated injury to human ciliated epithelium. Int J Infect Dis. 2007;11:11-5 pubmed
  73. Witzenrath M, Gutbier B, Hocke A, Schmeck B, Hippenstiel S, Berger K, et al. Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia. Crit Care Med. 2006;34:1947-54 pubmed
    ..Pneumolysin may play a central role for early-onset acute lung injury due to severe pneumococcal pneumonia by causing impairment of pulmonary microvascular barrier function and severe pulmonary hypertension. ..
  74. Ha U, Lim J, Jono H, Koga T, Srivastava A, Malley R, et al. A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae. J Immunol. 2007;178:1736-47 pubmed
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    ..These findings further demonstrate that the mechanism of pneumococcal pathogenesis is highly complex and multifactorial but ascribes a role for each of these virulence proteins, alone or in combination, in the process. ..
  76. Etuwewe O, Swann N, Hollingshead S, Tolmie H, Zijlstra E, Faragher B, et al. Effect of recurrent invasive pneumococcal disease on serum anti-pneumolysin IgG titres in HIV infected adults. Vaccine. 2009;27:3881-4 pubmed publisher
    ..95). High levels of anti-pneumolysin IgG do not predict protection from invasive pneumococcal disease or indicate that an effective immune response has occurred in HIV infected patients. ..
  77. Anderson R, Steel H, Cockeran R, Von Gottberg A, de Gouveia L, Klugman K, et al. 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. 2007;60:1155-8 pubmed
    ..Macrolides, at sub-MICs, but not other classes of antibiotic, subvert the production of pneumolysin, even in the presence of (and irrespective of the mechanism of) macrolide resistance in S. pneumoniae. ..
  78. Ebert S, Gerber J, Bader S, Mühlhauser F, Brechtel K, Mitchell T, et al. Dose-dependent activation of microglial cells by Toll-like receptor agonists alone and in combination. J Neuroimmunol. 2005;159:87-96 pubmed
    ..Costimulation with submaximum concentrations was additive or supraadditive, suggesting that even low concentrations of products of infectious agents can lead to microglial activation via TLRs. ..
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    ..These data show that antibiotic lysis of Streptococcus pneumoniae can be detrimental to the ciliated ependyma and that antipneumolysin antibody may have a therapeutic potential. ..
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    ..Further investigations are necessary to evaluate the effects of macrolides on macrolide-resistant Streptococcus pneumoniae. ..
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    ..In patient samples we showed that pneumolysin levels in CSF remained high after 48 hours in nonsurvivors of meningitis compared with survivors. Selective antipneumolysin treatment may present a novel therapeutic option. ..
  82. Iliev A, Djannatian J, Nau R, Mitchell T, Wouters F. Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin. Proc Natl Acad Sci U S A. 2007;104:2897-902 pubmed
    ..Thus, that our experiments show small GTPase activation by a cholesterol-dependent cytolysin suggests a membrane cholesterol-dependent activation mechanism. ..
  83. Bolotin S, Fuller J, Bast D, de Azavedo J. The two-component system sivS/R regulates virulence in Streptococcus iniae. FEMS Immunol Med Microbiol. 2007;51:547-54 pubmed
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  84. Ha U, Lim J, Kim H, Wu W, Jin S, Xu H, et al. MKP1 regulates the induction of MUC5AC mucin by Streptococcus pneumoniae pneumolysin by inhibiting the PAK4-JNK signaling pathway. J Biol Chem. 2008;283:30624-31 pubmed publisher
    ..These studies provide novel insights into the molecular mechanisms underlying the tight regulation of mucin overproduction in the pathogenesis of airway infectious diseases and may lead to development of new therapeutic strategies. ..
  85. Shoma S, Tsuchiya K, Kawamura I, Nomura T, Hara H, Uchiyama R, et al. Critical involvement of pneumolysin in production of interleukin-1alpha and caspase-1-dependent cytokines in infection with Streptococcus pneumoniae in vitro: a novel function of pneumolysin in caspase-1 activation. Infect Immun. 2008;76:1547-57 pubmed publisher
    ..pneumoniae than in those infected with the Deltaply mutant. These results clearly indicate that pneumolysin plays a key role in the host response to S. pneumoniae, particularly in the induction of caspase-1-dependent cytokines. ..
  86. Hirst R, Gosai B, Rutman A, Guerin C, Nicotera P, Andrew P, et al. Streptococcus pneumoniae deficient in pneumolysin or autolysin has reduced virulence in meningitis. J Infect Dis. 2008;197:744-51 pubmed publisher
    ..This study provides strong in vivo evidence that pneumolysin and autolysin play crucial roles in the pathogenesis of pneumococcal meningitis. ..