Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The pathogenesis of streptococcal infections: from Tooth decay to meningitis

Nature Reviews Microbiology volume 1, pages 219–230 (2003)Cite this article

Key Points

  • Streptococci are often carried on mucosal surfaces and skin without causing disease.

  • Streptococci can cause diseases that range from dental caries to necrotizing fasciitis. The type of disease caused depends on the virulence factors produced by the bacterium, as well as host susceptibility.

  • Streptococcus mutans causes dental caries; this requires the ability of this organism to form biofilms and to produce acid on the tooth surface.

  • Streptococcus agalactiae — group B streptococcus (GBS) — can cause neonatal meningitis. The organism is usually acquired by the neonate during passage through the birth canal of a colonized mother. Key virulence factors are the capsule, surface proteins and a haemolysin.

  • Streptococcus pyogenes — group A streptococcus (GAS) — can cause a wide range of diseases. Toxic-shock syndrome that is caused by this organism is mediated by the production of superantigens. The organism makes a capsule, a wide range of toxins and enzymes, and molecules that interfere with innate immunity.

  • Streptococcus pneumoniae (the pneumococcus) can cause pneumonia and meningitis. The organism induces overactivation of the inflammatory response, and disease symptoms partly reflect inappropriate production of host immune mediators. Key virulence factors are the capsule, surface proteins and pneumolysin.

  • Complete genome sequences are available for nine strains of these four species of streptococci (one for S. mutans, two for GBS, four for GAS and two for pneumococcus). Analysis of the genes present in all four species shows that the highly conserved genes are concerned with core function, such as nucleic-acid metabolism and protein synthesis. There is also significant variation in gene content, even between strains of the same species.

  • Simultaneous analysis of expression of all genes in the genome is now possible using microarray technology. It is also possible to examine the expression of genes in organisms that cause infection in model systems or in human disease. Such studies are beginning to allow an understanding of the detailed interactions that occur between pathogens and their hosts.

Abstract

The development of bacterial disease has been likened to a 'molecular arms race', in which the host tries to eliminate the bacteria, while the bacteria try to survive in the host. Although most bacteria do not cause disease, some cause serious human infection in a large proportion of encounters. Between these two extremes are bacteria that can coexist with humans in a carriage state but, under appropriate circumstances, cause disease. The streptococci exemplify this group of organisms, and by studying them we can begin to address why bacteria cause such a wide spectrum of disease.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Summary of the main virulence factors of four streptococcal species.
Figure 2: The complement system.
Figure 3: Genomic comparisons between streptococcal species.

References

  1. Loesche, W. J. Role of Streptococcus mutans in human dental decay. Microbiol. Rev. 50, 353–380 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Quivey, R. G., Kuhnert, W. L. & Hahn, K. Genetics of acid adaptation in oral streptococci. Crit. Rev. Oral Biol. Med. 12, 301–314 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Bhagwat, S. P., Nary, J. & Burne, R. A. Effects of mutating putative two-component systems on biofilm formation by Streptococcus mutans UA159. FEMS Microbiol. Lett. 205, 225–230 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Jenkinson, H. F. & Demuth, D. R. Structure, function and immunogenicity of streptococcal antigen I/II polypeptides. Mol. Microbiol. 23, 183–190 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Ma, J. K. et al. An investigation into the mechanism of protection by local passive immunization with monoclonal antibodies against Streptococcus mutans. Infect. Immun. 58, 3407–3414 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee, S. F. & Boran, T. L. Roles of sortase in surface expression of the major protein adhesin P1, saliva-induced aggregation and adherence, and cariogenicity of Streptococcus mutans. Infect. Immun. 71, 676–681 (2003). Describes the use of genetic manipulation in combination with an animal model to show the importance of the cell-surface anchoring of proteins in the ability of S. mutans to cause caries.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kuramitsu, H. K. Virulence factors of mutans streptococci: role of molecular genetics. Crit. Rev. Oral Biol. Med. 4, 159–176 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Hazlett, K. R. O., Michalek, S. M. & Banas, J. A. Inactivation of the gbpA gene of Streptococcus mutans increases virulence and promotes in vivo accumulation of recombinations between the glucosyltransferase B and C genes. Infect. Immun. 66, 2180–2185 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Munro, C., Michalek, S. M. & Macrina, F. L. Cariogenicity of Streptococcus mutans V403 glucosyltransferase and fructosyltransferase mutants constructed by allelic exchange. Infect. Immun. 59, 2316–2323 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Yamashita, Y., Bowen, W. H., Burne, R. A. & Kuramitsu, H. K. Role of the Streptococcus mutans gtf genes in caries induction in the specific-pathogen-free rat model. Infect. Immun. 61, 3811–3817 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Idone, V. et al. Effect of an orphan response regulator on Streptococcus mutans sucrose-dependent adherence and cariogenesis. Infect. Immun. 71, 4351–4360 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Russell, M., Harrington, D. & Russell, R. Identity of Streptococcus mutans surface protein antigen III and wall-associated protein antigen A. Infect. Immun. 63, 733–735 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kitten, T., Munro, C. L., Michalek, S. M. & Macrina, F. L. Genetic characterization of a Streptococcus mutans LraI family operon and role in virulence. Infect. Immun. 68, 4441–4451 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Haas, W. & Banas, J. A. Ligand-binding properties of the carboxyl-terminal repeat domain of Streptococcus mutans glucan-binding protein A. J. Bacteriol. 182, 728–733 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sato, Y., Yamamoto, Y. & Kizaki, H. Cloning and sequence analysis of the gbpC gene encoding a novel glucan-binding protein of Streptococcus mutans. Infect. Immun. 65, 668–675 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Holmes, A. R. et al. The pavA gene of Streptococcus pneumoniae encodes a fibronectin-binding protein that is essential for virulence. Mol. Microbiol. 41, 1395–1408 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Dintilhac, A., Alloing, G., Granadel, C. & Claverys, J. P. Competence and virulence of Streptococcus pneumoniae: Adc and PsaA mutants exhibit a requirement for Zn and Mn resulting from inactivation of putative ABC metal permeases. Mol. Microbiol. 25, 727–739 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Berry, A. M. & Paton, J. C. Sequence heterogeneity of PsaA, a 37-kilodalton putative adhesin essential for virulence of Streptococcus pneumoniae. Infect. Immun. 64, 5255–5262 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Marra, A. et al. In vivo characterization of the psa genes from Streptococcus pneumoniae in multiple models of infection. Microbiology 148, 1483–1491 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Romero-Steiner, S. et al. Inhibition of pneumococcal adherence to human nasopharyngeal epithelial cells by anti-PsaA antibodies. Clin. Diagn. Lab. Immunol. 10, 246–251 (2003).

    PubMed  PubMed Central  Google Scholar 

  21. Ajdić, D. I. et al. Genome sequence of Streptococcus mutans UA159, a cariogenic dental pathogen. Proc. Natl Acad. Sci. USA 99, 14434–14439 (2002). Contains a description of the S. mutans genome and an analysis of metabolic and regulatory aspects revealed by the genomic sequence.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schuchat, A. Group B streptococcal disease: from trials and tribulations to triumph and trepidation. Clin. Infect. Dis. 33, 751–756 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Schuchat, A. Epidemiology of Group B streptococcal disease in the United States: shifting paradigms. Clin. Microbiol. Rev. 11, 497–513 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rubens, C. E. et al. Respiratory epithelial cell invasion by group B streptococci. Infect. Immun. 60, 5157–5163 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gibson, R. L. et al. Group B streptococci invade endothelial cells: type III capsular polysaccharide attenuates invasion. Infect. Immun. 61, 478–485 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Jones, A. L., Knoll, K. M. & Rubens, C. E. Identification of Streptococcus agalactiae virulence genes in the neonatal rat sepsis model using signature-tagged mutagenesis. Mol. Microbiol. 37, 1444–1455 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Marques, M. B., Kasper, D. L., Pangburn, M. K. & Wessels, M. R. Prevention of C3 deposition by capsular polysaccharide is a virulence mechanism of type III group B streptococci. Infect. Immun. 60, 3986–3993 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Spellerberg, B. et al. Lmb, a protein with similarities to the LraI adhesin family, mediates attachment of Streptococcus agalactiae to human laminin. Infect. Immun. 67, 871–878 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Li, J. et al. Inactivation of the α C protein antigen gene, bca, by a novel shuttle/suicide vector results in attenuation of virulence and immunity in group B Streptococcus. Proc. Natl Acad. Sci. USA 94, 13251–13256 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schubert, A. et al. A fibrinogen receptor from group B Streptococcus. Mol. Microbiol. 46, 557–569 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Glaser, P. et al. Genome sequence of Streptococcus agalactiae. Mol. Microbiol. 45, 1499–1513 (2002). This paper and reference 147 describe the genome sequence of GBS, giving details of genomic structure, comparative genomics and metabolic insights from the two strains sequenced.

    Article  CAS  PubMed  Google Scholar 

  32. Chmouryguina, I., Suvorov, A., Ferrieri, P. & Cleary, P. Conservation of the C5a peptidase genes in group A and B streptococci. Infect. Immun. 64, 2387–2390 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Pritzlaff, C. A. et al. Genetic basis for the β-haemolytic/cytolytic activity of group B Streptococcus. Mol. Microbiol. 39, 236–248 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Nizet, V. et al. Group B streptococcal β-hemolysin expression is associated with injury of lung epithelial cells. Infect. Immun. 64, 3818–3826 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Gibson, R. L., Nizet, V. & Rubens, C. E. Group B streptococcal β-hemolysin promotes injury of lung microvascular endothelial cells. Pediatr. Res. 45, 626–634 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Nizet, V. et al. Invasion of brain microvascular endothelial cells by group B streptococci. Infect. Immun. 65, 5074–5081 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ring, A. et al. Group B streptococcal β-hemolysin induces nitric oxide production in murine macrophages. J. Infect. Dis. 182, 150–157 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Henneke, P. et al. Cellular activation, phagocytosis, and bactericidal activity against Group B Streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways. J. Immunol. 169, 3970–3977 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Doran, K. S. et al. Group B streptococcal β-hemolysin/cytolysin promotes invasion of human lung epithelial cells and the release of interleukin-8. J. Infect. Dis. 185, 196–203 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Nizet, V., Gibson, R. L. & Rubens, C. E. The role of group B streptococci β-hemolysin expression in newborn lung injury. Adv. Exp. Med. Biol. 418, 627–630 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Puliti, M. et al. Severity of group B streptococcal arthritis is correlated with β-hemolysin expression. J. Infect. Dis. 182, 824–832 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Ring, A. et al. Group B streptococcal β-hemolysin induces mortality and liver injury in experimental sepsis. J. Infect. Dis. 185, 1745–1753 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Bisno, A. L., Brito, M. O. & Collins, C. M. Molecular basis of group A streptococcal virulence. Lancet Infect. Dis. 3, 191–200 (2003). A detailed review of the virulence factors of S. pyogenes.

    Article  CAS  PubMed  Google Scholar 

  44. Courtney, H. S., Hasty, D. L. & Dale, J. B. Molecular mechanisms of adhesion, colonization, and invasion of group A streptococci. Ann. Med. 34, 77–87 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Hasty, D. L., Ofek, I., Courtney, H. S. & Doyle, R. J. Multiple adhesins of streptococci. Infect. Immun. 60, 2147–2152 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Okada, N., Liszewski, M., Atkinson, J. & Caparon, M. Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A Streptococcus. Proc. Natl Acad. Sci. USA 92, 2489–2493 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Talay, S. R. et al. Fibronectin-binding protein of Streptococcus pyogenes: sequence of the binding domain involved in adherence of streptococci to epithelial cells. Infect. Immun. 60, 3837–3844 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hanski, E., Horwitz, P. A. & Caparon, M. G. Expression of protein F, the fibronectin-binding protein of Streptococcus pyogenes JRS4, in heterologous streptococcal and enterococcal strains promotes their adherence to respiratory epithelial cells. Infect. Immun. 60, 5119–5125 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kreikemeyer, B., Talay, S. R. & Chhatwal, G. S. Characterization of a novel fibronectin-binding surface protein in group A streptococci. Mol. Microbiol. 17, 137–145 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Courtney, H., Dale, J. & Hasty, D. Differential effects of the streptococcal fibronectin-binding protein, FBP54, on adhesion of group A streptococci to human buccal cells and HEp-2 tissue culture cells. Infect. Immun. 64, 2415–2419 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Jaffe, J., Natanson-Yaron, S., Caparon, M. G. & Hanski, E. Protein F2, a novel fibronectin-binding protein from Streptococcus pyogenes, possesses two binding domains. Mol. Microbiol. 21, 373–384 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Rocha, C. L. & Fischetti, V. A. Identification and characterization of a novel fibronectin-binding protein on the surface of Group A streptococci. Infect. Immun. 67, 2720–2728 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Schrager, H. M. et al. Hyaluronic acid capsule modulates M protein-mediated adherence and acts as a ligand for attachment of group A Streptococcus to CD44 on human keratinocytes. J. Clin. Invest. 101, 1708–1716 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cywes, C. & Wessels, M. R. Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Nature 414, 648–652 (2001). Describes the role of the hyaluronic acid capsule of S. pyogenes in the interaction with CD44 on host cells and the importance of the subsequent signalling events

    Article  CAS  PubMed  Google Scholar 

  55. Horstmann, R. D., Sievertsen, H. J., Knobloch, J. & Fischetti, V. A. Antiphagocytic activity of streptococcal M protein: selective binding of complement control protein factor H. Proc. Natl Acad. Sci. USA 85, 1657–1661 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Johnsson, E. et al. Role of the hypervariable region in streptococcal M proteins: binding of a human complement inhibitor. J. Immunol. 161, 4894–4901 (1998).

    CAS  PubMed  Google Scholar 

  57. Whitnack, E. & Beachey, E. H. Inhibition of complement-mediated opsonization and phagocytosis of Streptococcus pyogenes by D fragments of fibrinogen and fibrin bound to cell surface M protein. J. Exp. Med. 162, 1983–1997 (1985).

    Article  CAS  PubMed  Google Scholar 

  58. Whitnack, E., Dale, J. B. & Beachey, E. H. Common protective antigens of group A streptococcal M proteins masked by fibrinogen. J. Exp. Med. 159, 1201–1212 (1984).

    Article  CAS  PubMed  Google Scholar 

  59. Berge, A., Kihlberg, B. -M., Sjoholm, A. G. & Bjorck, L. Streptococcal protein H forms soluble complement-activating complexes with IgG, but inhibits complement activation by IgG-coated targets. J. Biol. Chem. 272, 20774–20781 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Collin, M. et al. EndoS and SpeB from Streptococcus pyogenes inhibit immunoglobulin-mediated opsonophagocytosis. Infect. Immun. 70, 6646–6651 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cleary, P. P. et al. Streptococcal C5a peptidase is a highly specific endopeptidase. Infect. Immun. 60, 5219–5223 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Dale, J., Washburn, R., Marques, M. & Wessels, M. Hyaluronate capsule and surface M protein in resistance to opsonization of group A streptococci. Infect. Immun. 64, 1495–1501 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Lei, B. et al. Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis. Nature Med. 7, 1298–1305 (2001). Shows the importance of Mac in the ability of S. pyogenes to interfere with complement activation and phagocytosis. A mechanism is proposed for Mac function.

    Article  CAS  PubMed  Google Scholar 

  64. Zhou, M. J. & Brown, E. J. CR3 (Mac-1, αMβ2, CD11b/CD18) and Fc-γRIII cooperate in generation of a neutrophil respiratory burst: requirement for Fc-γRIII and tyrosine phosphorylation. J. Cell Biol. 125, 1407–1416 (1994).

    Article  CAS  PubMed  Google Scholar 

  65. Åkesson, P., Sjöholm, A. G. & Björck, L. Protein SIC, a novel extracellular protein of Streptococcus pyogenes interfering with complement function. J. Biol. Chem. 271, 1081–1088 (1996).

    Article  PubMed  Google Scholar 

  66. Fernie-King, B. A. et al. Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes. Immunology 103, 390–398 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fernie-King, B. A., Seilly, D. J., Davies, A. & Lachmann, P. J. Streptococcal inhibitor of complement inhibits two additional components of the mucosal innate immune system: secretory leukocyte proteinase inhibitor and lysozyme. Infect. Immun. 70, 4908–4916 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Frick, I. -M. et al. SIC, a secreted protein of Streptococcus pyogenes that inactivates antibacterial peptides. J. Biol. Chem. 278, 16561–16566 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Madden, J. C., Ruiz, N. & Caparon, M. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in Gram-positive bacteria. Cell 104, 143–152.

  70. Limbago, B., Penumalli, V., Weinrick, B. & Scott, J. R. Role of streptolysin O in a mouse model of invasive group A streptococcal disease. Infect. Immun. 68, 6384–6390 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fontaine, M. C., Lee, J. J. & Kehoe, M. A. Combined contributions of streptolysin O and streptolysin S to virulence of serotype M5 Streptococcus pyogenes strain Manfredo. Infect. Immun. 71, 3857–3865 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ofek, I., Zafriri, D., Goldhar, J. & Eisenstein, B. I. Inability of toxin inhibitors to neutralize enhanced toxicity caused by bacteria adherent to tissue culture cells. Infect. Immun. 58, 3737–3742 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Betschel, S. D. et al. Reduced virulence of group A streptococcal Tn916 mutants that do not produce streptolysin S. Infect. Immun. 66, 1671–1679 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Marrack, P. & Kappler, J. The staphylococcal enterotoxins and their relatives. Science 248, 1066 (1990).

    Article  CAS  PubMed  Google Scholar 

  75. Christner, R. et al. Identification of key gene products required for acquisition of plasmin-like enzymatic activity by group A streptococci. J. Infect. Dis. 175, 1115–1120 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Rasmussen, M., Muller, H. -P. & Bjorck, L. Protein GRAB of Streptococcus pyogenes regulates proteolysis at the bacterial surface by binding α2-macroglobulin. J. Biol. Chem. 274, 15336–15344 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Toppel, A. W. et al. Contribution of protein G-related α2-macroglobulin-binding protein to bacterial virulence in a mouse skin model of group A streptococcal infection. J. Infect. Dis. 187, 1694–1703 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Lukomski, S. et al. Genetic inactivation of an extracellular cysteine protease (SpeB) expressed by Streptococcus pyogenes decreases resistance to phagocytosis and dissemination to organs. Infect. Immun. 66, 771–776 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Saouda, M., Wu, W., Conran, P. & Boyle, M. D. Streptococcal pyrogenic exotoxin B enhances tissue damage initiated by other Streptococcus pyogenes products. J. Infect. Dis. 184, 723–731 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Collin, M. & Olsen, A. Effect of SpeB and EndoS from Streptococcus pyogenes on human immunoglobulins. Infect. Immun. 69, 7187–7189 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jonsson, S. et al. Phagocytosis and killing of common bacterial pathogens of the lung by human alveolar macrophages. J. Infect. Dis. 152, 4–13 (1985).

    Article  CAS  PubMed  Google Scholar 

  82. Polissi, A. et al. Large-scale identification of virulence genes from Streptococcus pneumoniae. Infect. Immun. 66, 5620–5629 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hava, D. & Camilli, A. Large-scale identificationof serotype 4 Streptococcus pneumoniae virulence factors. Mol. Microbiol. 45, 1389–1406 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lau, G. W. et al. A functional genomic analysis of type 3 Streptococcus pneumoniae virulence. Mol. Microbiol. 40, 555–571 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Cundell, D. R. et al. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 377, 435–438 (1995).

    Article  CAS  PubMed  Google Scholar 

  86. Tuomanen, E. et al. The induction of meningeal inflammation by components of the pneumococcal cell wall. J. Infect. Dis. 151, 859–868 (1985).

    Article  CAS  PubMed  Google Scholar 

  87. Canvin, J. R. et al. The role of pneumolysin and autolysin in the pathology of pneumonia and septicemia in mice infected with a type-2 pneumococcus. J. Infect. Dis. 2, 119–123 (1995).

    Article  Google Scholar 

  88. Alcantara, R. B., Preheim, L. C. & Gentry, M. J. Role of pneumolysin's complement-activating activity during pneumococcal bacteremia in cirrhotic rats. Infect. Immun. 67, 2862–2866 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Benton, K. A., Everson, M. P. & Briles, D. E. A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice. Infect. Immun. 63, 448–455 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Berry, A. M. et al. Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect. Immun. 57, 2037–2042 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Braun, J. S. et al. Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis. J. Clin. Invest. 109, 19–27 (2002). Gives details of the role and mechanism of pneumolysin and hydrogen peroxide in inducing brain damage during pneumococcal meninigitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Comis, S. D. et al. Cytotoxic effects on hair cells of guinea pig cochlea produced by pneumolysin, the thiol activated toxin of Streptococcus pneumoniae. Acta Otolaryngol. 113, 152–159 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. Johnson, M. K. The role of pneumolysin in ocular infections with Streptococcus pneumoniae. Curr. Eye Res. 9, 1107–1114 (1979).

    Article  Google Scholar 

  94. Houldsworth, S., Andrew, P. W. & Mitchell, T. J. Pneumolysin stimulates production of tumor necrosis factor α and interleukin-1β by human mononuclear phagocytes. Infect. Immun. 62, 1501–1503 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Braun, J. S. et al. Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide production from macrophages. Infect. Immun. 67, 3750–3756 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Cockeran, R. et al. Pneumolysin activates the synthesis and release of interleukin-8 by human neutrophils in vitro. J. Infect. Dis. 186, 562–565 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Cockeran, R. et al. Pneumolysin potentiates production of prostaglandin E-2 and leukotriene B-4 by human neutrophils. Infect. Immun. 69, 3494–3496 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rubins, J. B., Mitchell, T. J., Andrew, P. W. & Niewoehner, D. E. Pneumolysin activates phospholipase A in pulmonary artery endothelial cells. Infect. Immun. 62, 3829–3836 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Rubins, J. B. et al. Toxicity of pneumolysin to pulmonary alveolar epithelial cells. Infect. Immun. 61, 1352–1358 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Rubins, J. B., Duane, P. G., Charboneau, D. & Janoff, E. N. Toxicity of pneumolysin to pulmonary endothelial cells in vitro. Infect. Immun. 60, 1740–1746 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Steinfort, C. et al. Effect of Streptococcus pneumoniae on human respiratory epithelium in vitro. Infect. Immun. 57, 2006–2013 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Paton, J. C. & Ferrante, A. Inhibition of human polymorphonuclear leukocyte respiratory burst, bactericidal activity, and migration by pneumolysin. Infect. Immun. 41, 1212–1216 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Ferrante, A., Rowan-Kelly, B. & Paton, J. C. Inhibition of in vitro human lymphocyte response by the pneumococcal toxin pneumolysin. Infect. Immun. 46, 585–589 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Paton, J. C., Rowan-Kelly, B. & Ferrante, A. Activation of human complement by the pneumococcal toxin pneumolysin. Infect. Immun. 43, 1085–1087 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Rubins, J. B. et al. Distinct role for pneumolysin's cytotoxic and complement activities in the pathogenesis of pneumococcal pneumonia. Am. J. Respir. Crit. Care Med. 153, 1339–1346 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Hirst, R. A. et al. Relative roles of pneumolysin and hydrogen peroxide from Streptococcus pneumoniae in inhibition of ependymal ciliary beat frequency. Infect. Immun. 68, 1557–1562 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Stringaris, A. K. 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. 11, 355–368 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Malley, R. et al. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc. Natl Acad. Sci. USA 100, 1966–1971 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Crain, M. J. et al. Pneumococcal surface protein A (PspA) is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae. Infect. Immun. 58, 3293–3299 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. McDaniel, L. S. et al. Use of insertional inactivation to facilitate studies of biological properties of pneumococcal surface protein A (PspA). J. Exp. Med. 165, 381–394 (1987).

    Article  CAS  PubMed  Google Scholar 

  111. Neeleman, C. et al. Resistance to both complement activation and phagocytosis in type 3 pneumococci is mediated by the binding of complement regulatory protein factor H. Infect. Immun. 67, 4517–4524 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Tu, A. T. et al. Pneumococcal surface protein A inhibits complement activation by Streptococcus pneumoniae. Infect. Immun. 67, 4720–4724 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Hammerschmidt, S., Bethe, G., Remane, P. H. & Chhatwal, G. S. Identification of pneumococcal surface protein A as a lactoferrin-binding protein of Streptococcus pneumoniae. Infect. Immun. 67, 1683–1687 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Rosenow, C. et al. Contribution of a novel choline binding protein to adherence, colonization, and immunogenicity of Streptococcus pneumoniae. Mol. Microbiol. 25, 819–829 (1997).

    Article  CAS  PubMed  Google Scholar 

  115. Smith, B. L. & Hostetter, M. K. C3 as substrate for adhesion of Streptococcus pneumoniae. J. Infect. Dis. 182, 497–508 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Janulczyk, R. et al. Hic, a novel surface protein of Streptococcus pneumoniae that interferes with complement function. J. Biol. Chem. 275, 37257–37263 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Dave, S., Brooks-Walter, A., Pangburn, M. K. & McDaniel, L. S. PspC, a pneumococcal surface protein, binds human Factor H. Infect. Immun. 69, 3435–3437 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Madsen, M. et al. A pneumococcal protein that elicits interleukin-8 from pulmonary epithelial cells. J. Infect. Dis. 181, 1330–1336 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Zhang, J. R. et al. The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell 102, 827–837 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Berry, A. M., Lock, R. A., Hansman, D. & Paton, J. C. Contribution of autolysin to virulence of Streptococcus pneumoniae. Infect. Immun. 57, 2324–2330 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Gosink, K. K. et al. Role of novel choline binding proteins in virulence of Streptococcus pneumoniae. Infect. Immun. 68, 5690–5695 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tettelin, H. et al. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science 293, 498–506 (2001). Highlights the differences between the stains and shows the ability of the organism to transport many sugars.

    Article  CAS  PubMed  Google Scholar 

  123. Humphrey, J. H. Hyaluronidase production by pneumococci. J. Pathol. Bacteriol. 55, 273–275 (1948).

    Google Scholar 

  124. Berry, A. M. & Paton, J. C. Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the genes encoding pneumolysin and other putative pneumococcal virulence proteins. Infect. Immun. 68, 133–140 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Camara, M., Boulnois, G. J., Andrew, P. W. & Mitchell, T. J. A neuraminidase from Streptococcus pneumoniae has the features of a surface protein. Infect. Immun. 62, 3688–3695 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Tong, H. H., Blue, L. E., James, M. A. & DeMaria, T. F. Evaluation of the virulence of a Streptococcus pneumoniae neuraminidase-deficient mutant in nasopharyngeal colonization and development of otitis media in the chinchilla model. Infect. Immun. 68, 921–924 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Winter, A. J. et al. 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, 4411–4418 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kharat, A. S. & Tomasz, A. Inactivation of the srtA gene affects localization of surface proteins and decreases adhesion of Streptococcus pneumoniae to human pharyngeal cells in vitro. Infect. Immun. 71, 2758–2765 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Lawrence, M. C. et al. The crytal structure of pneumococcal surface antigen PsaA reveals a metal-binding site and a novel structure for a putative ABC-type binding protein. Structure 6, 1553–1561 (1998).

    Article  CAS  PubMed  Google Scholar 

  130. Tseng, H. -J., McEwan, A. G., Paton, J. C. & Jennings, M. P. Virulence of Streptococcus pneumoniae: PsaA mutants are hypersensitive to oxidative stress. Infect. Immun. 70, 1635–1639 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bergmann, S. et al. Identification of a novel plasmin(ogen)-binding motif in surface displayed α-enolase of Streptococcus pneumoniae. Mol. Microbiol. 49, 411–423 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Yesilkaya, H. et al. Role of manganese-containing superoxide dismutase in oxidative stress and virulence of Streptococcus pneumoniae. Infect. Immun. 68, 2819–2826 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Auzat, I. et al. The NADH oxidase of Streptococcus pneumoniae: its involvement in competence and virulence. Mol. Microbiol. 34, 1018–1028 (1999).

    Article  CAS  PubMed  Google Scholar 

  134. Duane, P. G., Rubins, J. B., Weisel, H. R. & Janoff, E. N. Identification of hydrogen peroxide as a Streptococcus pneumoniae toxin for rat alveolar epithelial cells. Infect. Immun. 61, 4392–4397 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Brown, J. S., Gilliland, S. M. & Holden, D. W. A Streptococcus pneumoniae pathogenicity island encoding an ABC transporter involved in iron uptake and virulence. Mol. Microbiol. 40, 572–585 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Peterson, J. D. et al. The Comprehensive Microbial Resource. Nucleic Acids Res. 29, 123–125 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Smoot, L. M. et al. Characterization of two novel pyrogenic toxin superantigens made by an acute rheumatic fever clone of Streptococcus pyogenes associated with multiple disease outbreaks. Infect. Immun. 70, 7095–7104 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lei, B. et al. Opsonophagocytosis-inhibiting Mac protein of group A Streptococcus: identification and characteristics of two genetic complexes. Infect. Immun. 70, 6880–6890 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Banks, D. J., Beres, S. B. & Musser, J. M. The fundamental contribution of phages to GAS evolution, genome diversification and strain emergence. Trends Microbiol. 10, 515–521 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Smoot, J. C. et al. Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks. Proc. Natl Acad. Sci. USA 99, 4668–4673 (2002). This paper and references 148, 149 and 150 describe the genome sequences of four strains of GAS. These studies describe the genomic organization of the strains, microarray analysis of strains associated with acute rheumatic fever, and provide an insight into the role of phages and genomic rearrangements in virulence.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Voyich, J. M. et al. Genome-wide protective response used by group A Streptococcus to evade destruction by human polymorphonuclear leukocytes. Proc. Natl Acad. Sci. USA 100, 1996–2001 (2003). Analysis of genome-wide gene-expression changes on interaction of GAS with human polymorphonuclear cells. Confirmation of the role of a two-component system in virulence and that this system is upregulated during human infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Graham, M. R. et al. Virulence control in group A Streptococcus by a two-component gene regulatory system: global expression profiling and in vivo infection modeling. Proc. Natl Acad. Sci. USA 99, 13855–13860 (2002). Global expression profiling in GAS using microarrays to examine the control of virulence gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Virtaneva, K. et al. Group A Streptococcus gene expression in humans and cynomolgus macaques with acute pharyngitis. Infect. Immun. 71, 2199–2207 (2003). Examination of gene expression in GAS when associated with pharyngitis. Use of human samples and an animal model to measure gene expression during the disease process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kihlberg, B. M. et al. Biological properties of a Streptococcus pyogenes mutant generated by Tn916 insertion in mga. Microb. Pathog. 19, 299–315 (1995).

    Article  CAS  PubMed  Google Scholar 

  145. Fournier, B., Klier, A. & Rapoport, G. The two-component system ArlS–ArlR is a regulator of virulence gene expression in Staphylococcus aureus. Mol. Microbiol. 41, 247–261 (2001).

    Article  CAS  PubMed  Google Scholar 

  146. Tettelin, H. et al. Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococcus agalactiae. Proc. Natl Acad. Sci. USA 99, 12391–12396 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Beres, S. B. et al. Genome sequence of a serotype M3 strain of group A Streptococcus: phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proc. Natl Acad. Sci. USA 99, 10078–10083 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ferretti, J. J. et al. Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc. Natl Acad. Sci. USA 98, 4658–4663 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Nakagawa, I. et al. Genome sequence of an M3 strain of Streptococcus pyogenes reveals a large-scale genomic rearrangement in invasive strains and new insights into phage evolution. Genome Res. 13, 1042–1055 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hoskins, J. et al. Genome of the bacterium Streptococcus pneumoniae strain R6. J. Bacteriol. 183, 5709–5717 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    Timothy J. Mitchell

Authors
  1. Timothy J. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

Entrez

CylE

EndoS

FBP54

FbsA

GRAB

Lmb

M-protein

pneumolysin

PsaA

PspA

PspC

SLO

SloC

SpaP

SpeB

FURTHER INFORMATION

Comprehensive Microbial Resource

Infectious disease information

GAS

GBS

Streptococcus pneumoniae

Tim Mitchell's web site

Glossary

ENDOCARDITIS

Inflammation of the lining of the heart and its valves.

TWO-COMPONENT SIGNAL-TRANSDUCTION PATHWAY

A signal-transduction system that consists of a sensor protein that senses and responds to an external signal, and which acts on a response-regulator protein that transmits the signal to other components of the cell.

LECTIN

A cell-agglutinating protein of non-immune origin, which binds carbohydrates without modifying them.

PASSIVE IMMUNIZATION

The induction of immunity by the transfer of immunoglobulins or T cells.

SORTASE

An enzyme that links proteins to the cell wall.

HYDROXYAPATITE

The main mineral component of teeth.

GLUCOSYLTRANSFERASE

Any hexosyltransferase enzyme for which the glycosyl group transferred is glucosyl.

GERM-FREE RATS

Rats bred and maintained in such conditions that they contain no microorganisms.

SIGNATURE-TAGGED MUTAGENESIS

A negative selection method for the identification of virulence genes. The technique involves mutation of microbial genes by random insertion of a tagged transposon. After growth of a mixed population in a host, mutated genes that are absent and hence required for virulence are identified with the help of the tag.

OPSONOPHAGOCYTOSIS

Increased uptake of bacteria by host cells due to binding of antibody or complement.

β-HAEMOLYSIS

Zone of clearing around bacterial colonies grown on blood agar, caused by lysis of red blood cells.

HAEMOLYSIN

Material that lyses red blood cells.

ENDOGLYCOSIDASE

An enzyme that hydrolyses non-terminal glycosidic linkages in oligosaccharides or polysaccharides.

MEMBRANE-ATTACK COMPLEX

A collection of late complement components that damage the cell membrane.

PYOGENIC EXOTOXINS

Toxins that induce fever.

SUPERANTIGEN

A protein that activates T cells non-specifically.

STREPTOCOCCAL TOXIC-SHOCK SYNDROME

A disease associated with decreased blood pressure and multi-organ failure.

EPENDYMAL CILIA

Specialized ciliated cells that line the ventricles of the brain.

ENOLASE

Also known as phosphopyruvate hydratase. An enzyme that catalyses the conversion of 2-phospho-D-glycerate to phosphoenolpyruvate and water.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mitchell, T. The pathogenesis of streptococcal infections: from Tooth decay to meningitis. Nat Rev Microbiol 1, 219–230 (2003). https://doi.org/10.1038/nrmicro771

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro771

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing