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.

  • Review Article
  • Published:

Molecular insight into invasive group A streptococcal disease

Nature Reviews Microbiology volume 9, pages 724–736 (2011)Cite this article

Subjects

Key Points

  • Streptococcus pyogenes, also called group A Streptococcus (GAS), is a Gram-positive bacterial pathogen that naturally infects only humans and is the aetiological agent of several potentially fatal syndromes, including 'flesh-eating disease' (necrotizing fasciitis).

  • The worldwide resurgence of severe invasive GAS infections over the past 30 years is correlated with the global dissemination of the GAS serotype M1T1 clone.

  • Recent work demonstrates that the capacity of GAS serotype M1T1 to cause invasive disease is increased by selection for mutations within the covRS two-component regulator operon. This genetic alteration dramatically changes the transcriptome, resulting in the downregulation of a broad-spectrum cysteine protease, streptococcal pyrogenic exotoxin B (SpeB), and the upregulation of several virulence factors, including the nuclease extracellular streptodornase D (Sda1).

  • Elevated Sda1 nuclease activity enhances the resistance of GAS serotype M1T1 to neutrophil-mediated killing, through the degradation of DNA-based neutrophil extracellular traps, and the absence of SpeB protease activity permits the accumulation of plasmin activity on the GAS cell surface, triggering tissue destruction and systemic spread.

  • GAS uses a repertoire of virulence factors to thwart the host innate immune response, and several of these factors are critical for invasive disease. The switch from non-invasive to hyperinvasive GAS is triggered by particular genetic events, and our increased understanding of this switch has led to a model for the initiation of invasive GAS disease in humans.

  • An understanding of the mechanism by which GAS causes serious invasive infections may augment the development of new-generation therapeutics and provide better health outcomes in the fight against this globally important human pathogen.

Abstract

Streptococcus pyogenes is also known as group A Streptococcus (GAS) and is an important human pathogen that causes considerable morbidity and mortality worldwide. The GAS serotype M1T1 clone is the most frequently isolated serotype from life-threatening invasive (at a sterile site) infections, such as streptococcal toxic shock-like syndrome and necrotizing fasciitis. Here, we describe the virulence factors and newly discovered molecular events that mediate the in vivo changes from non-invasive GAS serotype M1T1 to the invasive phenotype, and review the invasive-disease trigger for non-M1 GAS. Understanding the molecular basis and mechanism of initiation for streptococcal invasive disease may expedite the discovery of novel therapeutic targets for the treatment and control of severe invasive GAS diseases.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The repertoire of virulence factors expressed by group A Streptococcus serotype M1T1 cells that disable neutrophils.
Figure 2: Proposed model for the initiation and progression of infections with severe invasive group A Streptococcus serotype M1T1.

Similar content being viewed by others

References

  1. Carapetis, J. R., Steer, A. C., Mulholland, E. K. & Weber, M. The global burden of group A streptococcal diseases. Lancet Infect. Dis. 5, 685–694 (2005).

    Article  PubMed  Google Scholar 

  2. Cunningham, M. W. Pathogenesis of group A streptococcal infections. Clin. Microbiol. Rev. 13, 470–511 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Young, M. H., Aronoff, D. M. & Engleberg, N. C. Necrotizing fasciitis: pathogenesis and treatment. Expert Rev. Anti. Infect. Ther. 3, 279–294 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Cole, J. N., Henningham, A., Gillen, C. M., Ramachandran, V. & Walker, M. J. Human pathogenic streptococcal proteomics and vaccine development. Proteomics Clin. Appl. 2, 387–410 (2008). An overview of streptococcal proteomics and the selection of antigens as novel vaccine candidates.

    Article  CAS  PubMed  Google Scholar 

  5. Beall, B., Facklam, R. & Thompson, T. Sequencing emm-specific PCR products for routine and accurate typing of group A streptococci. J. Clin. Microbiol. 34, 953–958 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Shulman, S. T. et al. Group A streptococcal pharyngitis serotype surveillance in North America, 2000–2002 Clin. Infect. Dis. 39, 325–332 (2004).

    Article  PubMed  Google Scholar 

  7. Steer, A. C., Law, I., Matatolu, L., Beall, B. W. & Carapetis, J. R. Global emm type distribution of group A streptococci: systematic review and implications for vaccine development. Lancet Infect. Dis. 9, 611–616 (2009).

    Article  PubMed  Google Scholar 

  8. Aziz, R. K. & Kotb, M. Rise and persistence of global M1T1 clone of Streptococcus pyogenes. Emerg. Infect. Dis. 14, 1511–1517 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tart, A. H., Walker, M. J. & Musser, J. M. New understanding of the group A Streptococcus pathogenesis cycle. Trends Microbiol. 15, 318–325 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Sumby, P. et al. Evolutionary origin and emergence of a highly successful clone of serotype M1 group A Streptococcus involved multiple horizontal gene transfer events. J. Infect. Dis. 192, 771–782 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Sumby, P., Whitney, A. R., Graviss, E. A., DeLeo, F. R. & Musser, J. M. Genome-wide analysis of group A streptococci reveals a mutation that modulates global phenotype and disease specificity. PLoS Pathog. 2, e5 (2006). The original report demonstrating that phenotypic changes in GAS serotype M1T1 are caused solely by mutations within the covRS two-component regulator operon.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Walker, M. J. et al. DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nature Med. 13, 981–985 (2007). The first demonstration that the nuclease Sda1 provides selection pressure for the emergence of covRS mutants of GAS serotype M1T1 in vivo.

    Article  CAS  PubMed  Google Scholar 

  13. Pence, M. A. et al. Streptococcal inhibitor of complement promotes innate immune resistance phenotypes of invasive M1T1 group A Streptococcus. J. Innate Immun. 2, 587–595 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Engleberg, N. C., Heath, A., Miller, A., Rivera, C. & DiRita, V. J. Spontaneous mutations in the csrRS two component regulatory system of Streptococcus pyogenes result in enhanced virulence in a murine model of skin and soft tissue infection. J. Infect. Dis. 183, 1043–1054 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Zinkernagel, A. S. et al. The IL-8 protease SpyCEP/ScpC of group A Streptococcus promotes resistance to neutrophil killing. Cell Host Microbe 4, 170–178 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Timmer, A. M. et al. Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis. J. Biol. Chem. 284, 862–871 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sumby, P. et al. Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response. Proc. Natl Acad. Sci. USA 102, 1679–1684 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Buchanan, J. T. et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr. Biol. 16, 396–400 (2006). The demonstration that the nuclease Sda1 enhances GAS serotype M1T1 resistance to neutrophil killing through the destruction of NETs.

    Article  CAS  PubMed  Google Scholar 

  19. Kansal, R. G., McGeer, A., Low, D. E., Norrby-Teglund, A. & Kotb, M. Inverse relation between disease severity and expression of the streptococcal cysteine protease, SpeB, among clonal M1T1 isolates recovered from invasive group A streptococcal infection cases. Infect. Immun. 68, 6362–6369 (2000). An epidemiological study documenting that clinical GAS isolates from severe invasive infections exhibit less SpeB protease activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Aziz, R. K. et al. Invasive M1T1 group A Streptococcus undergoes a phase-shift in vivo to prevent proteolytic degradation of multiple virulence factors by SpeB. Mol. Microbiol. 51, 123–134 (2004). Proteomic analyses showing that covRS mutations results in the downregulation of SpeB protease activity and the upregulation of multiple GAS serotype M1T1 virulence factors.

    Article  CAS  PubMed  Google Scholar 

  21. Cole, J. N. et al. Trigger for group A streptococcal M1T1 invasive disease. FASEB J. 20, 1745–1747 (2006). The first report to document that a loss of SpeB activity through covRS mutation permits the accumulation of cell surface protease activity and subsequent GAS serotype M1T1 dissemination in vivo.

    Article  CAS  PubMed  Google Scholar 

  22. Lamagni, T. L. et al. Epidemiology of severe Streptococcus pyogenes disease in Europe. J. Clin. Microbiol. 46, 2359–2367 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. O'Grady, K. A. et al. The epidemiology of invasive group A streptococcal disease in Victoria, Australia. Med. J. Aust. 186, 565–569 (2007).

    PubMed  Google Scholar 

  24. O'Loughlin, R. E. et al. The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000–2004. Clin. Infect. Dis. 45, 853–862 (2007).

    Article  PubMed  Google Scholar 

  25. Sharkawy, A. et al. Severe group A streptococcal soft-tissue infections in Ontario: 1992–1996. Clin. Infect. Dis. 34, 454–460 (2002).

    Article  PubMed  Google Scholar 

  26. 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 

  27. Nobbs, A. H., Lamont, R. J. & Jenkinson, H. F. Streptococcus adherence and colonization. Microbiol. Mol. Biol. Rev. 73, 407–450 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Abbot, E. L. et al. Pili mediate specific adhesion of Streptococcus pyogenes to human tonsil and skin. Cell. Microbiol. 9, 1822–1833 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Kreikemeyer, B., Klenk, M. & Podbielski, A. The intracellular status of Streptococcus pyogenes: role of extracellular matrix-binding proteins and their regulation. Int. J. Med. Microbiol. 294, 177–188 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    CAS  PubMed  Google Scholar 

  31. Okada, N., Liszewski, M. K., Atkinson, J. P. & 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 

  32. Horstmann, R. D., Sievertsen, H. J., Leippe, M. & Fischetti, V. A. Role of fibrinogen in complement inhibition by streptococcal M protein. Infect. Immun. 60, 5036–5041 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Carlsson, F., Berggard, K., Stalhammar-Carlemalm, M. & Lindahl, G. Evasion of phagocytosis through cooperation between two ligand-binding regions in Streptococcus pyogenes M protein. J. Exp. Med. 198, 1057–1068 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Staali, L., Bauer, S., Morgelin, M., Bjorck, L. & Tapper, H. Streptococcus pyogenes bacteria modulate membrane traffic in human neutrophils and selectively inhibit azurophilic granule fusion with phagosomes. Cell. Microbiol. 8, 690–703 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Lauth, X. et al. M1 protein allows group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition. J. Innate Immun. 1, 202–214 (2009). A report describing the finding that M1 protein enhances bacterial survival of neutrophil-mediated killing through inhibition of human antimicrobial peptides.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ashbaugh, C. D., Warren, H. B., Carey, V. J. & Wessels, M. R. Molecular analysis of the role of the group A streptococcal cysteine protease, hyaluronic acid capsule, and M protein in a murine model of human invasive soft-tissue infection. J. Clin. Invest. 102, 550–560 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dale, J. B. & Chiang, E. C. Intranasal immunization with recombinant group A streptococcal M protein fragment fused to the B subunit of Escherichia coli labile toxin protects mice against systemic challenge infections. J. Infect. Dis. 171, 1038–1041 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Bober, M., Enochsson, C., Collin, M. & Morgelin, M. Collagen VI is a subepithelial adhesive target for human respiratory tract pathogens. J. Innate Immun. 2, 160–166 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Crater, D. L. & van de Rijn, I. Hyaluronic acid synthesis operon (has) expression in group A streptococci. J. Biol. Chem. 270, 18452–18458 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. 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 

  41. Wessels, M. R., Moses, A. E., Goldberg, J. B. & DiCesare, T. J. Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci. Proc. Natl Acad. Sci. USA 88, 8317–8321 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cole, J. N. et al. M protein and hyaluronic acid are essential for in vivo selection of covRS mutations characteristic of invasive M1T1 group A Streptococcus. mBio 1, e00191–00110 (2010). The first demonstration that M1 protein and the hyaluronic acid capsule are essential for the invasive phenotype of GAS serotype M1T1 in vivo.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Moses, A. et al. Relative contributions of hyaluronic acid capsule and M protein to virulence in a mucoid strain of the group A Streptococcus. Infect. Immun. 65, 64–71 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bhakdi, S., Tranum-Jensen, J. & Sziegoleit, A. Mechanism of membrane damage by streptolysin-O. Infect. Immun. 47, 52–60 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Bricker, A. L., Cywes, C., Ashbaugh, C. D. & Wessels, M. R. NAD+-glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci. Mol. Microbiol. 44, 257–269 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Hakansson, A., Bentley, C. C., Shakhnovic, E. A. & Wessels, M. R. Cytolysin-dependent evasion of lysosomal killing. Proc. Natl Acad. Sci. USA 102, 5192–5197 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Brosnahan, A. J., Mantz, M. J., Squier, C. A., Peterson, M. L. & Schlievert, P. M. Cytolysins augment superantigen penetration of stratified mucosa. J. Immunol. 182, 2364–2373 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. 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 

  51. 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 3, e3455 (2008).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Edwards, R. J. et al. Specific C-terminal cleavage and inactivation of interleukin-8 by invasive disease isolates of Streptococcus pyogenes. J. Infect. Dis. 192, 783–790 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Kurupati, P. et al. Chemokine-cleaving Streptococcus pyogenes protease SpyCEP is necessary and sufficient for bacterial dissemination within soft tissues and the respiratory tract. Mol. Microbiol. 76, 1387–1397 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Turner, C. E., Kurupati, P., Wiles, S., Edwards, R. J. & Sriskandan, S. Impact of immunization against SpyCEP during invasive disease with two streptococcal species: Streptococcus pyogenes and Streptococcus equi. Vaccine 27, 4923–4929 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Turner, C. E., Kurupati, P., Jones, M. D., Edwards, R. J. & Sriskandan, S. Emerging role of the interleukin-8 cleaving enzyme SpyCEP in clinical Streptococcus pyogenes infection. J. Infect. Dis. 200, 555–563 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. 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 

  57. 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 

  58. Fernie-King, B. A., Seilly, D. J. & Lachmann, P. J. The interaction of streptococcal inhibitor of complement (SIC) and its proteolytic fragments with the human beta defensins. Immunology 111, 444–452 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Frick, I. M., Akesson, P., Rasmussen, M., Schmidtchen, A. & Bjorck, L. SIC, a secreted protein of Streptococcus pyogenes that inactivates antibacterial peptides. J. Biol. Chem. 278, 16561–16566 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. von Pawel-Rammingen, U., Johansson, B. P. & Bjorck, L. IdeS, a novel streptococcal cysteine proteinase with unique specificity for immunoglobulin G. EMBO J. 21, 1607–1615 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Trevino, J. et al. CovS simultaneously activates and inhibits the CovR-mediated repression of distinct subsets of group A Streptococcus virulence factor-encoding genes. Infect. Immun. 77, 3141–3149 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhu, H., Liu, M., Sumby, P. & Lei, B. The secreted esterase of group A Streptococcus is important for invasive skin infection and dissemination in mice. Infect. Immun. 77, 5225–5232 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Boyle, M. D. & Lottenberg, R. Plasminogen activation by invasive human pathogens. Thromb. Haemost. 77, 1–10 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Coleman, J. L. & Benach, J. L. Use of the plasminogen activation system by microorganisms. J. Lab. Clin. Med. 134, 567–576 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Werb, Z. ECM and cell surface proteolysis: regulating cellular ecology. Cell 91, 439–442 (1997).

    Article  CAS  PubMed  Google Scholar 

  67. Svensson, M. D., Sjobring, U., Luo, F. & Bessen, D. E. Roles of the plasminogen activator streptokinase and the plasminogen-associated M protein in an experimental model for streptococcal impetigo. Microbiology 148, 3933–3945 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Khil, J. et al. Plasminogen enhances virulence of group A streptococci by streptokinase-dependent and streptokinase-independent mechanisms. J. Infect. Dis. 188, 497–505 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Li, Z., Ploplis, V. A., French, E. L. & Boyle, M. D. Interaction between group A streptococci and the plasmin(ogen) system promotes virulence in a mouse skin infection model. J. Infect. Dis. 179, 907–914 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Lahteenmaki, K., Kuusela, P. & Korhonen, T. K. Bacterial plasminogen activators and receptors. FEMS Microbiol. Rev. 25, 531–552 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Sun, H. et al. Plasminogen is a critical host pathogenicity factor for group A streptococcal infection. Science 305, 1283–1286 (2004). A report showing that human plasminogen is activated to plasmin on the GAS cell surface, allowing the destruction of host tissue barriers and triggering systemic spread.

    Article  CAS  PubMed  Google Scholar 

  72. Pancholi, V., Fontan, P. & Jin, H. Plasminogen-mediated group A streptococcal adherence to and pericellular invasion of human pharyngeal cells. Microb. Pathog. 35, 293–303 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Derbise, A., Song, Y. P., Parikh, S., Fischetti, V. A. & Pancholi, V. Role of the C-terminal lysine residues of streptococcal surface enolase in Glu- and Lys-plasminogen-binding activities of group A streptococci. Infect. Immun. 72, 94–105 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Berge, A. & Sjobring, U. PAM, a novel plasminogen-binding protein from Streptococcus pyogenes. J. Biol. Chem. 268, 25417–25424 (1993).

    CAS  PubMed  Google Scholar 

  75. Sanderson-Smith, M. L. et al. M protein-mediated plasminogen binding is essential for the virulence of an invasive Streptococcus pyogenes isolate. FASEB J. 22, 2715–2722 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Pancholi, V. & Fischetti, V. A. α-Enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci. J. Biol. Chem. 273, 14503–14515 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Cork, A. J. et al. Defining the structural basis of human plasminogen binding by streptococcal surface enolase. J. Biol. Chem. 284, 17129–17137 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pancholi, V. & Fischetti, V. A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J. Exp. Med. 176, 415–426 (1992).

    Article  CAS  PubMed  Google Scholar 

  79. Lottenberg, R. et al. Cloning, sequence analysis, and expression in Escherichia coli of a streptococcal plasmin receptor. J. Bacteriol. 174, 5204–5210 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. McKay, F. C. et al. Plasminogen binding by group A streptococcal isolates from a region of hyperendemicity for streptococcal skin infection and a high incidence of invasive infection. Infect. Immun. 72, 364–370 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wang, H., Lottenberg, R. & Boyle, M. D. A role for fibrinogen in the streptokinase-dependent acquisition of plasmin(ogen) by group A streptococci. J. Infect. Dis. 171, 85–92 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Wang, H., Lottenberg, R. & Boyle, M. D. Analysis of the interaction of group A streptococci with fibrinogen, streptokinase and plasminogen. Microb. Pathog. 18, 153–166 (1995).

    Article  CAS  PubMed  Google Scholar 

  83. Lottenberg, R., Minning-Wenz, D. & Boyle, M. D. Capturing host plasmin(ogen): a common mechanism for invasive pathogens? Trends Microbiol. 2, 20–24 (1994).

    Article  CAS  PubMed  Google Scholar 

  84. Lijnen, H. R. et al. Mechanisms of plasminogen activation. J. Intern. Med. 236, 415–424 (1994).

    Article  CAS  PubMed  Google Scholar 

  85. Herwald, H. et al. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 116, 367–379 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Walker, M. J., McArthur, J. D., McKay, F. & Ranson, M. Is plasminogen deployed as a Streptococcus pyogenes virulence factor? Trends Microbiol. 13, 308–313 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Hytonen, J., Haataja, S., Gerlach, D., Podbielski, A. & Finne, J. The SpeB virulence factor of Streptococcus pyogenes, a multifunctional secreted and cell surface molecule with strepadhesin, laminin-binding and cysteine protease activity. Mol. Microbiol. 39, 512–519 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Chaussee, M. S., Liu, J., Stevens, D. L. & Ferretti, J. J. Genetic and phenotypic diversity among isolates of Streptococcus pyogenes from invasive infections. J. Infect. Dis. 173, 901–908 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. Chaussee, M. S., Phillips, E. R. & Ferretti, J. J. Temporal production of streptococcal erythrogenic toxin B (streptococcal cysteine proteinase) in response to nutrient depletion. Infect. Immun. 65, 1956–1959 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Loughman, J. A. & Caparon, M. Regulation of SpeB in Streptococcus pyogenes by pH and NaCl: a model for in vivo gene expression. J. Bacteriol. 188, 399–408 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Musser, J., Stockbauer, K., Kapur, V. & Rudgers, G. Substitution of cysteine 192 in a highly conserved Streptococcus pyogenes extracellular cysteine protease (interleukin 1β convertase) alters proteolytic activity and ablates zymogen processing. Infect. Immun. 64, 1913–1917 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Shelburne, S. A. 3rd et al. Growth characteristics of and virulence factor production by group A Streptococcus during cultivation in human saliva. Infect. Immun. 73, 4723–4731 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Eriksson, A. & Norgren, M. Cleavage of antigen-bound immunoglobulin G by SpeB contributes to streptococcal persistence in opsonizing blood. Infect. Immun. 71, 211–217 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Nyberg, P., Rasmussen, M. & Bjorck, L. α2-Macroglobulin-proteinase complexes protect Streptococcus pyogenes from killing by the antimicrobial peptide LL-37. J. Biol. Chem. 279, 52820–52823 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Ringdahl, U. et al. A role for the fibrinogen-binding regions of streptococcal M proteins in phagocytosis resistance. Mol. Microbiol. 37, 1318–1326 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Kansal, R. G., Nizet, V., Jeng, A., Chuang, W. J. & Kotb, M. Selective modulation of superantigen-induced responses by streptococcal cysteine protease. J. Infect. Dis. 187, 398–407 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Raeder, R., Woischnik, M., Podbielski, A. & Boyle, M. D. A secreted streptococcal cysteine protease can cleave a surface-expressed M1 protein and alter the immunoglobulin binding properties. Res. Microbiol. 149, 539–548 (1998).

    Article  CAS  PubMed  Google Scholar 

  98. Chatellier, S. et al. Genetic relatedness and superantigen expression in group A Streptococcus serotype M1 isolates from patients with severe and nonsevere invasive diseases. Infect. Immun. 68, 3523–3534 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hollands, A. et al. A naturally occurring mutation in ropB suppresses SpeB expression and reduces M1T1 group A streptococcal systemic virulence. PLoS ONE 3, e4102 (2008).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  100. Ikebe, T. et al. Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates. PLoS Pathog. 6, e1000832 (2010).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  101. Carroll, R. K. et al. Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice. J. Clin. Invest. 121, 1956–1968 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Aziz, R. K. et al. Mosaic prophages with horizontally acquired genes account for the emergence and diversification of the globally disseminated M1T1 clone of Streptococcus pyogenes. J. Bacteriol. 187, 3311–3318 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dalton, T., Collins, J., Barnett, T. & Scott, J. RscA, a member of the MDR1 family of transporters, is repressed by CovR and required for growth of Streptococcus pyogenes under heat stress. J. Bacteriol. 188, 77–85 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Shea, P. R. et al. Distinct signatures of diversifying selection revealed by genome analysis of respiratory tract and invasive bacterial populations. Proc. Natl Acad. Sci. USA 108, 5039–5044 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Dalton, T. L. & Scott, J. R. CovS inactivates CovR and is required for growth under conditions of general stress in Streptococcus pyogenes. J. Bacteriol. 186, 3928–3937 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Froehlich, B., Bates, C. & Scott, J. Streptococcus pyogenes CovR/S mediates growth in iron starvation and in the presence of the human cationic antimicrobial peptide LL-37. J. Bacteriol. 191, 673–677 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Sawai, J. et al. Growth phase-dependent effect of clindamycin on production of exoproteins by Streptococcus pyogenes. Antimicrob. Agents Chemother. 51, 461–467 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Gryllos, I., Levin, J. C. & Wessels, M. R. The CsrR/CsrS two-component system of group A Streptococcus responds to environmental Mg2+. Proc. Natl Acad. Sci. USA 100, 4227–4232 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Levin, J. & Wessels, M. Identification of csrR/csrS, a genetic locus that regulates hyaluronic acid capsule synthesis in group A Streptococcus. Mol. Microbiol. 30, 209–219 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Heath, A., DiRita, V. J., Barg, N. L. & Engleberg, N. C. A two-component regulatory system, CsrR-CsrS, represses expression of three Streptococcus pyogenes virulence factors, hyaluronic acid capsule, streptolysin S, and pyrogenic exotoxin B. Infect. Immun. 67, 5298–5305 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Graham, M. R. et al. Group A Streptococcus transcriptome dynamics during growth in human blood reveals bacterial adaptive and survival strategies. Am. J. Pathol. 166, 455–465 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Churchward, G. The two faces of Janus: virulence gene regulation by CovR/S in group A streptococci. Mol. Microbiol. 64, 34–41 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Kansal, R. G. et al. Dissection of the molecular basis for hypervirulence of an in vivo-selected phenotype of the widely disseminated M1T1 strain of group A Streptococcus bacteria. J. Infect. Dis. 201, 855–865 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Aziz, R. K. et al. Microevolution of group A streptococci in vivo: capturing regulatory networks engaged in sociomicrobiology, niche adaptation, and hypervirulence. PLoS ONE 5, e9798 (2010).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  115. Svensson, M. D. et al. Role for a secreted cysteine proteinase in the establishment of host tissue tropism by group A streptococci. Mol. Microbiol. 38, 242–253 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Hassell, M., Fagan, P., Carson, P. & Currie, B. J. Streptococcal necrotising fasciitis from diverse strains of Streptococcus pyogenes in tropical northern Australia: case series and comparison with the literature. BMC Infect. Dis. 4, 60 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Husmann, L. K., Yung, D. L., Hollingshead, S. K. & Scott, J. R. Role of putative virulence factors of Streptococcus pyogenes in mouse models of long-term throat colonization and pneumonia. Infect. Immun. 65, 1422–1430 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Ravins, M. et al. Characterization of a mouse passaged, highly encapsulated variant of group A Streptococcus in in vitro and in vivo studies. J. Infect. Dis. 182, 1702–1711 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Courtney, H. S., Ofek, I. & Hasty, D. L. M protein mediated adhesion of M type 24 Streptococcus pyogenes stimulates release of interleukin-6 by HEp-2 tissue culture cells. FEMS Microbiol. Lett. 151, 65–70 (1997).

    Article  CAS  PubMed  Google Scholar 

  120. Miyoshi-Akiyama, T. et al. Use of DNA arrays to identify a mutation in the negative regulator, csrR, responsible for the high virulence of a naturally occurring type M3 group A Streptococcus clinical isolate. J. Infect. Dis. 193, 1677–1684 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. 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 

  122. Maamary, P. G. et al. Parameters governing invasive disease propensity of non-M1 serotype group A streptococci. J. Innate Immun. 2, 596–606 (2010). The first report of non-M1 GAS undergoing covRS mutations in vivo , but at a reduced frequency compared with GAS serotype M1T1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sugareva, V. et al. Serotype- and strain-dependent contribution of the sensor kinase CovS of the CovRS two-component system to Streptococcus pyogenes pathogenesis. BMC Microbiol. 10, 34 (2010).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  124. Hollands, A. et al. Genetic switch to hypervirulence reduces colonization phenotypes of the globally disseminated group A Streptococcus M1T1 Clone. J. Infect. Dis. 202, 11–19 (2010). A study showing that covRS mutants of GAS serotype M1T1 have a colonization defect compared with wild-type bacteria.

    Article  CAS  PubMed  Google Scholar 

  125. Lembke, C. et al. Characterization of biofilm formation by clinically relevant serotypes of group A streptococci. Appl. Environ. Microbiol. 72, 2864–2875 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Marcon, M. J. et al. Occurrence of mucoid M-18 Streptococcus pyogenes in a central Ohio pediatric population. J. Clin. Microbiol. 26, 1539–1542 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Stollerman, G. H. & Dale, J. B. The importance of the group A Streptococcus capsule in the pathogenesis of human infections: a historical perspective. Clin. Infect. Dis. 46, 1038–1045 (2008).

    Article  PubMed  Google Scholar 

  128. Hoe, N. P. et al. Distribution of streptococcal inhibitor of complement variants in pharyngitis and invasive isolates in an epidemic of serotype M1 group A Streptococcus infection. J. Infect. Dis. 183, 633–639 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Hasegawa, T. et al. Detection of invasive protein profile of Streptococcus pyogenes M1 isolates from pharyngitis patients. APMIS 118, 167–178 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Garcia, A. F. et al. An insert in the covS gene distinguishes a pharyngeal and a blood isolate of Streptococcus pyogenes found in the same individual. Microbiology 156, 3085–3095 (2010). The first report to document the covRS mutations of GAS serotype M81.0 in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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 

  132. Bryant, A. E., Bayer, C. R., Huntington, J. D. & Stevens, D. L. Group A streptococcal myonecrosis: increased vimentin expression after skeletal-muscle injury mediates the binding of Streptococcus pyogenes. J. Infect. Dis. 193, 1685–1692 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. McNeil, S. A. et al. Safety and immunogenicity of 26-valent group A Streptococcus vaccine in healthy adult volunteers. Clin. Infect. Dis. 41, 1114–1122 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Choby, B. A. Diagnosis and treatment of streptococcal pharyngitis. Am. Fam. Physician 79, 383–390 (2009).

    PubMed  Google Scholar 

  135. Danchin, M. H. et al. Burden of acute sore throat and group A streptococcal pharyngitis in school-aged children and their families in Australia. Pediatrics 120, 950–957 (2007).

    Article  PubMed  Google Scholar 

  136. Danchin, M. H. et al. The burden of group A streptococcal pharyngitis in Melbourne families. Indian J. Med. Res. 119 (Suppl.), 144–147 (2004).

    PubMed  Google Scholar 

  137. Steer, A. C. et al. Prospective surveillance of streptococcal sore throat in a tropical country. Pediatr. Infect. Dis. J. 28, 477–482 (2009).

    Article  PubMed  Google Scholar 

  138. Nandi, S., Kumar, R., Ray, P., Vohra, H. & Ganguly, N. K. Group A streptococcal sore throat in a periurban population of northern India: a one-year prospective study. Bull. World Health Organ. 79, 528–533 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Bernard, P. Management of common bacterial infections of the skin. Curr. Opin. Infect. Dis. 21, 122–128 (2008).

    Article  PubMed  Google Scholar 

  140. Koning, S. et al. Impetigo: incidence and treatment in Dutch general practice in 1987 and 2001—results from two national surveys. Br. J. Dermatol. 154, 239–243 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Steer, A. C. et al. High burden of impetigo and scabies in a tropical country. PLoS Negl. Trop. Dis. 3, e467 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Wong, L. C. et al. Outcome of an interventional program for scabies in an Indigenous community. Med. J. Aust. 175, 367–370 (2001).

    CAS  PubMed  Google Scholar 

  143. Steer, A. C. & Carapetis, J. R. Prevention and treatment of rheumatic heart disease in the developing world. Nature Rev. Cardiol. 6, 689–698 (2009).

    Article  Google Scholar 

  144. Carapetis, J. R., Currie, B. J. & Mathews, J. D. Cumulative incidence of rheumatic fever in an endemic region: a guide to the susceptibility of the population? Epidemiol. Infect. 124, 239–244 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Grover, A. et al. Epidemiology of rheumatic fever and rheumatic heart disease in a rural community in northern India. Bull. World Health Organ. 71, 59–66 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Lennon, D., Stewart, J., Farrell, E., Palmer, A. & Mason, H. School-based prevention of acute rheumatic fever: a group randomized trial in New Zealand. Pediatr. Infect. Dis. J. 28, 787–794 (2009).

    Article  PubMed  Google Scholar 

  147. Seckeler, M. D., Barton, L. L. & Brownstein, R. The persistent challenge of rheumatic fever in the Northern Mariana Islands. Int. J. Infect. Dis. 14, e226–e229.

  148. Ahn, S. Y. & Ingulli, E. Acute poststreptococcal glomerulonephritis: an update. Curr. Opin. Pediatr. 20, 157–162 (2008).

    Article  PubMed  Google Scholar 

  149. WHO. The current evidence for the burden of group A streptococcal diseases. WHO [online], (2005).

  150. Becquet, O. et al. Acute post-streptococcal glomerulonephritis in children of French Polynesia: a 3-year retrospective study. Pediatr. Nephrol. 25, 275–280 (2010).

    Article  PubMed  Google Scholar 

  151. Lappin, E. & Ferguson, A. J. Gram-positive toxic shock syndromes. Lancet Infect. Dis. 9, 281–290 (2009).

    Article  CAS  PubMed  Google Scholar 

  152. Lamagni, T. L. et al. Severe Streptococcus pyogenes infections, United Kingdom, 2003–2004. Emerg. Infect. Dis. 14, 202–209 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Norton, R. et al. Invasive group A streptococcal disease in North Queensland (1996–2001). Indian J. Med. Res. 119 (Suppl), 148–151 (2004).

    PubMed  Google Scholar 

  154. Le Hello, S. et al. Clinical and microbial characteristics of invasive Streptococcus pyogenes disease in New Caledonia, a region in Oceania with a high incidence of acute rheumatic fever. J. Clin. Microbiol. 48, 526–530 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. Steer, A. C. et al. Prospective surveillance of invasive group A streptococcal disease, Fiji, 2005–2007. Emerg. Infect. Dis. 15, 216–222 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Sriskandan, S. & Altmann, D. M. The immunology of sepsis. J. Pathol. 214, 211–223 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Stevens, D. L. Invasive group A Streptococcus infections. Clin. Infect. Dis. 14, 2–11 (1992).

    Article  CAS  PubMed  Google Scholar 

  158. van der Helm-van Mil, A. H. Acute rheumatic fever and poststreptococcal reactive arthritis reconsidered. Curr. Opin. Rheumatol. 22, 437–442 (2010).

    Article  PubMed  Google Scholar 

  159. van Dillen, J., Zwart, J., Schutte, J. & van Roosmalen, J. Maternal sepsis: epidemiology, etiology and outcome. Curr. Opin. Infect. Dis. 23, 249–254 (2010).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the Australian National Health and Medicine Research Council and the US National Institutes of Health for their funding support.

Author information

Authors and Affiliations

  1. Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, 92093-0687, California, USA

    Jason N. Cole & Victor Nizet

  2. School of Chemistry and Molecular Biosciences and the Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, 4072, QLD, Australia

    Jason N. Cole, Timothy C. Barnett & Mark J. Walker

  3. Rady Children's Hospital, 3020 Children's Way, San Diego, 92123, California, USA

    Victor Nizet

Authors
  1. Jason N. Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy C. Barnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor Nizet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark J. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark J. Walker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1

Switching mutations observed in covRS in GAS from human isolates and murine models of invasive infections (PDF 399 kb)

Related links

Related links

FURTHER INFORMATION

Mark J. Walker's homepage

Glossary

Rheumatic fever

An inflammatory disease caused by cross-reactive antibodies that are induced after a streptococcal infection.

Acute glomerulonephritis

Inflammation of the glomeruli of the kidney that follows streptococcal infection and is caused by a build-up of immune complexes.

Necrotizing fasciitis

Commonly known as flesh-eating disease; an infection of the skin, causing destruction of underlying tissues and muscle.

Cathelicidin

A mammalian cationic antimicrobial polypeptide with an important role in host innate immunity and prevention of bacterial infections.

Membrane attack complex

An assemblage of complement proteins that forms pores across cell membranes, resulting in cell death.

α-defensins

A family of mammalian cationic antimicrobial peptides that are secreted by leukocytes and inhibit the activity of serine proteases.

Lysozyme

A mammalian muramidase that catalyses the hydrolysis of bacterial cell walls.

Subcutaneous-chamber infection model

A disease model system that uses micropore teflon diffusion chambers which are subcutaneously implanted into mice to enable the post-infection recovery of bacteria and immune infiltrate.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cole, J., Barnett, T., Nizet, V. et al. Molecular insight into invasive group A streptococcal disease. Nat Rev Microbiol 9, 724–736 (2011). https://doi.org/10.1038/nrmicro2648

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2648

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

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