Chapter 5 : Toxins and Superantigens of Group A Streptococci

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(group A streptococcus) is a remarkable and versatile human bacterial pathogen that is capable of producing an impressive arsenal of both surface-expressed and secreted virulence factors. This pathogen continues to generate significant morbidity by causing a variety of uncomplicated human diseases such as pharyngitis and skin infections, and more serious diseases such as acute rheumatic and scarlet fevers. In addition, group A streptococci cause some of the most devastating bacterial diseases known, such as necrotizing fasciitis/myositis and the streptococcal toxic shock syndrome (STSS). This chapter focuses on the true exotoxins of group A streptococci with regard to their structure, function, and genetics, as well as their roles in the pathogenesis of human disease. The streptococcal superantigens belong to a larger group of structurally conserved exotoxins that are also produced by coagulase-positive staphylococci. Some group C and group G beta-hemolytic streptococci also produce these toxins. The exotoxins discussed in the chapter are streptococcal pyrogenic toxin type B (SpeB, or cysteine protease), streptococcal pyrogenic toxin type F (SpeF, or mitogenic factor), streptococcal cytolytic toxins, streptokinase, and streptococcal inhibitor of complement (Sic). It has been reported that uncharacterized Spes exist, and they have also been detected in certain group B, C, F, and G streptococcal strains that may mimic the role of the group A streptococcal Spes.

Citation: McCormick J, Peterson M, Schlievert P. 2006. Toxins and Superantigens of Group A Streptococci, p 47-58. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch5
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() Structure conservation and models of T-cell activation complexes for streptococcal superantigens. (A) Ribbon diagrams of the crystal structures for streptococcal pyrogenic exotoxin serotypes A, C, H, J, streptococcal superantigen (SSA), and streptococcal mitogenic exotoxin-Z(SMEZ) ( ). (B) Ribbon diagrams demonstrating typical antigen-mediated T-cell activation (left) ( ) and modeled T-cell activation complexes for SpeA (middle) and SpeC (right). The co-crystal structures of SpeA and SpeC in complex with their respective TCR β-chains ( ) and of SpeC in complex with the MHC class II through the zinc-dependent high-affinity binding domain have been determined ( ). In light of recent evidence ( ), it is likely that SpeC also activates T cells in a mode similar to the staphylococcal enterotoxin A model ( ) where the superantigen also engages MHC class II through the generic low-affinity binding domain. The binding architecture for the generic low-affinity MHC class II binding to SpeA and SpeC is modeled using the staphylococcal enterotoxin B-MHC class II co-crystal structure ( ). Note the presence of the zinc ion (magenta) coordinated in the high-affinity binding site for SpeC and that SpeA lacks this zinc site. The TCR α-chain (shown in gray) for both the SpeA and SpeC diagrams is modeled for clarity by superimposition of The α/β TCR shown on the left to the respective TCR β-chains for both superantigens. The figure was generated using Pymol ( ).

Citation: McCormick J, Peterson M, Schlievert P. 2006. Toxins and Superantigens of Group A Streptococci, p 47-58. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch5
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The presence of the high-affinity, zinc-dependent MHC class II binding domain is associated with approximately 100-fold higher potency of streptococcal superantigens. (A) Sodium dodecyl sulfate polyacrylamide gel demonstrating purity of eight recombinant serotypes of streptococcal superantigens expressed and purified from . Techniques for cloning, expression, and purification have been described ( ). (B) Standard human T-cell proliferation assay using H-thymidine of the eight recombinant streptococcal superantigens. SpeC, SpeG, SpeH, SpeI, SpeJ, and SMEZeach contain the predicted zinc-binding motif found in the β-grasp domain. SpeA and SSA lack this motif and are no longer active at ∼100-fold concentrations higher than the zinc-binding motif containing superantigens. cpm, counts per minute.

Citation: McCormick J, Peterson M, Schlievert P. 2006. Toxins and Superantigens of Group A Streptococci, p 47-58. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch5
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1. Akesson, P.,, A. G. Sjoholm,, and L. Bjorck. 1996. Protein SIC, a novel extracellular protein of Streptococcus pyogenes interfering with complement function. J. Biol. Chem. 271: 1081 1088.
2. Andersen, P. S.,, P. M. Lavoie,, R. P. Sekaly,, H. Churchill,, D. M. Kranz,, P. M. Schlievert,, K. Karjalainen,, and R. A. Mariuzza. 1999. Role of the T cell receptor alpha chain in stabilizing TCR-superantigen-MHC class II complexes. Immunity 10: 473 483.
3. Arcus, V. L.,, T. Proft,, J. A. Sigrell,, H. M. Baker,, J. D. Fraser,, and E. N. Baker. 2000. Conservation and variation in superantigen structure and activity highlighted by the three-dimensional structures of two new superantigens from Streptococcus pyogenes. J. Mol. Biol. 299: 157 168.
4. Artiushin, S. C.,, J. F. Timoney,, A. S. Sheoran,, and S. K. Muthupalani. 2002. Characterization and immunogenicity of pyrogenic mitogens SePE-H and SePE-I of Streptococcus equi. Microb. Pathog. 32: 71 85.
5. Ashbaugh, C. D.,, H. B. Warren,, V. J. Carey,, and M. R. Wessels. 1998. 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. Investig. 102: 550 560.
6. Assimacopoulos, A. P.,, J. A. Stoehr,, and P. M. Schlievert. 1997. Mitogenic factors from group G streptococci associated with scarlet fever and streptococcal toxic shock syndrome. Adv. Exp. Med. Biol. 418: 109 114.
7. Baker, H. M.,, T. Proft,, P. D. Webb,, V. L. Arcus,, J. D. Fraser,, and E. N. Baker. 2004. Crystallographic and mutational data show that the streptococcal pyrogenic exotoxin J can use a common binding surface for T-cell receptor binding and dimerization. J. Biol. Chem. 279: 38571 38576.
8. Banks, D. J.,, S. B. Beres,, and J. M. Musser. 2002. The fundamental contribution of phages to GAS evolution, genome diversification and strain emergence. Trends Microbiol. 10: 515 521.
9. Banks, D. J.,, S. F. Porcella,, K. D. Barbian,, S. B. Beres,, L. E. Philips,, J. M. Voyich,, F. R. DeLeo,, J. M. Martin,, G. A. Somerville,, and J. M. Musser. 2004. Progress toward characterization of the group A Streptococcus metagenome: complete genome sequence of a macrolide-resistant serotype M6 strain. J. Infect. Dis. 190: 727 738.
10. Basma, H.,, A. Norrby-Teglund,, Y. Guedez,, A. McGeer,, D. E. Low,, O. El-Ahmedy,, B. Schwartz,, and M. Kotb. 1999. Risk factors in the pathogenesis of invasive group A streptococcal infections: role of protective humoral immunity. Infect. Immun. 67: 1871 1877.
11. Beres, S. B.,, G. L. Sylva,, K. D. Barbian,, B. Lei,, J. S. Hoff,, N. D. Mammarella,, M. Y. Liu,, J. C. Smoot,, S. F. Porcella,, L. D. Parkins,, D. S. Campbell,, T. M. Smith,, J. K. McCormick,, D. Y. Leung,, P. M. Schlievert,, and J. M. Musser. 2002. 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.
12. Berge, A.,, and L. Bjorck. 1995. Streptococcal cysteine proteinase releases biologically active fragments of streptococcal surface proteins. J. Biol. Chem. 270: 9862 9867.
13. Bessen, D. E.,, M. W. Izzo,, T. R. Fiorentino,, R. M. Caringal,, S. K. Hollingshead,, and B. Beall. 1999. Genetic linkage of exotoxin alleles and emm gene markers for tissue tropism in group A streptococci. J. Infect. Dis. 179: 627 636.
14. Betschel, S. D.,, S. M. Borgia,, N. L. Barg,, D. E. Low,, and J. C. De Azavedo. 1998. Reduced virulence of group A streptococcal Tn916 mutants that do not produce streptolysin S. Infect. Immun. 66: 1671 1679.
15. Bhakdi, S.,, J. Tranum-Jensen,, and A. Sziegoleit. 1985. Mechanism of membrane damage by streptolysin-O. Infect. Immun. 47: 52 60.
16. Bhakdi, S.,, H. Bayley,, A. Valeva,, I. Walev,, B. Walker,, M. Kehoe,, and M. Palmer. 1996. Staphylococcal alpha-toxin, streptolysin-O, and Escherichia coli hemolysin: prototypes of pore-forming bacterial cytolysins. Arch. Microbiol. 165: 73 79.
17. Binks, M.,, and K. S. Sriprakash. 2004. Characterization of a complement-binding protein, DRS, from strains of Streptococcus pyogenes containing the emm12 and emm55 genes. Infect. Immun. 72: 3981 3986.
18. Blomster-Hautamaa, D. A.,, and P. M. Schlievert. 1988. Preparation of toxic shock syndrome toxin-1. Methods Enzymol. 165: 37 43.
19. Bohach, G. A.,, D. J. Fast,, R. D. Nelson,, and P. M. Schlievert. 1990. Staphylococcal and streptococcal pyrogenic toxins involved in toxic shock syndrome and related illnesses. Crit. Rev. Microbiol. 17: 251 272.
20. Bohach, G. A.,, A. R. Hauser,, and P. M. Schlievert. 1988. Cloning of the gene, speB, for streptococcal pyrogenic exotoxin type B in Escherichia coli. Infect. Immun. 56: 1665 1667.
21. Burns, E. H., Jr.,, S. Lukomski,, J. Rurangirwa,, A. Podbielski,, and J. M. Musser. 1998. Genetic inactivation of the extracellular cysteine protease enhances in vitro internalization of group A streptococci by human epithelial and endothelial cells. Microb. Pathog. 24: 333 339.
22. Burns, E. H., Jr.,, A. M. Marciel,, and J. M. Musser. 1996. Activation of a 66-kilodalton human endothelial cell matrix metalloprotease by Streptococcus pyogenes extracellular cysteine protease. Infect. Immun. 64: 4744 4750.
23. Bustin, M.,, M. C. Lin,, W. H. Stein,, and S. Moore. 1970. Activity of the reduced zymogen of streptococcal proteinase. J. Biol. Chem. 245: 846 849.
24. Carr, A.,, D. D. Sledjeski,, A. Podbielski,, M. D. Boyle,, and B. Kreikemeyer. 2001. Similarities between complement-mediated and streptolysin S-mediated hemolysis. J. Biol. Chem. 276: 41790 41796.
25. Chaussee, M. S.,, E. R. Phillips,, and J. J. Ferretti. 1997. Temporal production of streptococcal erythrogenic toxin B (streptococcal cysteine proteinase) in response to nutrient depletion. Infect. Immun. 65: 1956 1959.
26. Cleary, P. P.,, E. L. Kaplan,, J. P. Handley,, A. Wlazlo,, M. H. Kim,, A. R. Hauser,, and P. M. Schlievert. 1992. Clonal basis for resurgence of serious Streptococcus pyogenes disease in the 1980s. Lancet 339: 518 521.
27. Cockerill, F. R., 3rd, K. L. MacDonald, R. L. Thompson, F. Roberson, P. C. Kohner, J. Besser-Wiek, J. M. Manahan, J. M. Musser, P. M. Schlievert, J. Talbot, B. Frankfort, J. M. Steckelberg,W. R.Wilson, and M. T. Osterholm. 1997. An outbreak of invasive group A streptococcal disease associated with high carriage rates of the invasive clone among school-aged children. JAMA 277: 38 43.
28. Collin, M.,, and A. Olsen. 2003. Extracellular enzymes with immunomodulating activities: variations on a theme in Streptococcus pyogenes. Infect. Immun. 71: 2983 2992.
29. Colon, A. E.,, R. M. Cole,, and C. G. Leonard. 1972. Intergroup lysis and transduction by streptococcal bacteriophages. J. Virol. 9: 551 553.
30. Colon, A. E.,, R. M. Cole,, and C. G. Leonard. 1971. Lysis and lysogenization of groups A, C, and G streptococci by a transducing bacteriophage induced from a group G Streptococcus. J. Virol. 8: 103 110.
31. Cone, L. A.,, D. R. Woodard,, P. M. Schlievert,, and G. S. Tomory. 1987. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N. Engl. J. Med. 317: 146 149.
32. DeLano, W. L. 2002. The PyMOL molecular graphics system on World Wide Web. http://www.pymol.org.
33. Demers, B.,, A. E. Simor,, H. Vellend,, P. M. Schlievert,, S. Byrne,, F. Jamieson,, S. Walmsley,, and D. E. Low. 1993. Severe invasive group A streptococcal infections in Ontario, Canada: 1987-1991. Clin. Infect. Dis. 16: 792 800.
34. Dinges, M. M.,, and P. M. Schlievert. 2001. Comparative analysis of lipopolysaccharide-induced tumor necrosis factor alpha activity in serum and lethality in mice and rabbits pretreated with the staphylococcal superantigen toxic shock syndrome toxin 1. Infect. Immun. 69: 7169 7172.
35. Dinges, M. M.,, and P. M. Schlievert. 2001. Role of T cells and gamma interferon during induction of hypersensitivity to lipopolysaccharide by toxic shock syndrome toxin 1 in mice. Infect. Immun. 69: 1256 1264.
36. Doran, J. D.,, M. Nomizu,, S. Takebe,, R. Menard,, D. Griffith,, and E. Ziomek. 1999. Autocatalytic processing of the streptococcal cysteine protease zymogen: processing mechanism and characterization of the autoproteolytic cleavage sites. Eur. J. Biochem. 263: 145 151.
37. Earhart, C. A.,, G. M. Vath,, M. Roggiani,, P. M. Schlievert,, and D. H. Ohlendorf. 2000. Structure of streptococcal pyrogenic exotoxin A reveals a novel metal cluster. Protein Sci. 9: 1847 1851.
38. Eriksson, A.,, B. Eriksson,, S. E. Holm,, and M. Norgren. 1999. Streptococcal DNase B is immunologically identical to superantigen SpeF but involves separate domains. Clin. Diagn. Lab. Immunol. 6: 133 136.
39. Eriksson, A.,, and M. Norgren. 1999. The superantigenic activity of streptococcal pyrogenic exotoxin B is independent of the protease activity. FEMS Immunol. Med. Microbiol. 25: 355 363.
40. Eriksson, B. K.,, J. Andersson,, S. E. Holm,, and M. Norgren. 1999. Invasive group A streptococcal infections: T1M1 isolates expressing pyrogenic exotoxins A and B in combination with selective lack of toxin-neutralizing antibodies are associated with increased risk of streptococcal toxic shock syndrome. J. Infect. Dis. 180: 410 418.
41. Fast, D. J.,, P. M. Schlievert,, and R. D. Nelson. 1989. Toxic shock syndrome-associated staphylococcal and streptococcal pyrogenic toxins are potent inducers of tumor necrosis factor production. Infect. Immun. 57: 291 294.
42. Fernie-King, B. A.,, D. J. Seilly,, A. Davies,, and P. J. Lachmann. 2002. 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.
43. Fernie-King, B. A.,, D. J. Seilly,, and P. J. Lachmann. 2004. The interaction of streptococcal inhibitor of complement (SIC) and its proteolytic fragments with the human beta defensins. Immunology 111: 444 452.
44. Fernie-King, B. A.,, D. J. Seilly,, C. Willers,, R. Wurzner,, A. Davies,, and P. J. Lachmann. 2001. Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes. Immunology 103: 390 398.
45. Ferretti, J. J.,, W. M. McShan,, D. Ajdic,, D. J. Savic,, G. Savic,, K. Lyon,, C. Primeaux,, S. Sezate,, A. N. Suvorov,, S. Kenton,, H. S. Lai,, S. P. Lin,, Y. Qian,, H. G. Jia,, F. Z. Najar,, Q. Ren,, H. Zhu,, L. Song,, J. White,, X. Yuan,, S.W. Clifton,, B. A. Roe,, and R. McLaughlin. 2001. Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc. Natl. Acad. Sci. USA 98: 4658 4663.
46. Fields, B. A.,, E. L. Malchiodi,, H. Li,, X. Ysern,, C. V. Stauffacher,, P. M. Schlievert,, K. Karjalainen,, and R. A. Mariuzza. 1996. Crystal structure of a T-cell receptor beta-chain complexed with a superantigen. Nature 384: 188 192.
47. Fontaine, M. C.,, J. J. Lee,, and M. A. Kehoe. 2003. Combined contributions of streptolysin O and streptolysin S to virulence of serotype M5 Streptococcus pyogenes strain Manfredo. Infect. Immun. 71: 3857 3865.
48. Frick, I. M.,, P. Akesson,, M. Rasmussen,, A. Schmidtchen,, and L. Bjorck. 2003. SIC, a secreted protein of Streptococcus pyogenes that inactivates antibacterial peptides. J. Biol. Chem. 278: 16561 16566.
49. Frobisher, M.,, and J. H. Brown. 1927. Transmissible toxigenicity of streptococci. Bull. Johns Hopkins Hosp. 41: 167 173.
50. Ginsburg, I. 1972. Mechanisms of cell and tissue injury induced by group A streptococci: relation to poststreptococcal sequelae. J. Infect. Dis. 126: 294 340.
51. Goshorn, S. C.,, G. A. Bohach,, and P. M. Schlievert. 1988. Cloning and characterization of the gene, speC, for pyrogenic exotoxin type C from Streptococcus pyogenes. Mol. Gen. Genet. 212: 66 70.
52. Hacker, J.,, and J. B. Kaper. 2000. Pathogenicity islands and the evolution of microbes. Annu. Rev. Microbiol. 54: 641 679.
53. Hauser, A. R.,, and P. M. Schlievert. 1990. Nucleotide sequence of the streptococcal pyrogenic exotoxin type B gene and relationship between the toxin and the streptococcal proteinase precursor. J. Bacteriol. 172: 4536 4542.
54. Hauser, A. R.,, D. L. Stevens,, E. L. Kaplan,, and P. M. Schlievert. 1991. Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome. J. Clin. Microbiol. 29: 1562 1567.
55. Hennecke, J.,, A. Carfi,, and D. C. Wiley. 2000. Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1. EMBO J. 19: 5611 5624.
56. Herwald, H.,, M. Collin,, W. Muller-Esterl,, and L. Bjorck. 1996. Streptococcal cysteine proteinase releases kinins: a virulence mechanism. J. Exp. Med. 184: 665 673.
57. Hoe, N. P.,, P. Kordari,, R. Cole,, M. Liu,, T. Palzkill,, W. Huang,, D. McLellan,, G. J. Adams,, M. Hu,, J. Vuopio-Varkila,, T. R. Cate,, M. E. Pichichero,, K. M. Edwards,, J. Eskola,, D. E. Low,, and J. M. Musser. 2000. Human immune response to streptococcal inhibitor of complement, a serotype M1 group A Streptococcus extracellular protein involved in epidemics. J. Infect. Dis. 182: 1425 1436.
58. Hoe, N. P.,, K. Nakashima,, S. Lukomski,, D. Grigsby,, M. Liu,, P. Kordari,, S. J. Dou,, X. Pan,, J. Vuopio-Varkila,, S. Salmelinna,, A. McGeer,, D. E. Low,, B. Schwartz,, A. Schuchat,, S. Naidich,, D. De Lorenzo,, Y. X. Fu,, and J. M. Musser. 1999. Rapid selection of complement-inhibiting protein variants in group A Streptococcus epidemic waves. Nat. Med. 5: 924 929.
59. Holm, S. E.,, A. Norrby,, A. M. Bergholm,, and M. Norgren. 1992. Aspects of pathogenesis of serious group A streptococcal infections in Sweden, 1988-1989. J. Infect. Dis. 166: 31 37.
60. Hryniewicz, W.,, and J. Pryjma. 1977. Effect of streptolysin S on human and mouse T and B lymphocytes. Infect. Immun. 16: 730 733.
61. Iwasaki, M.,, H. Igarashi,, Y. Hinuma,, and T. Yutsudo. 1993. Cloning, characterization and overexpression of a Streptococcus pyogenes gene encoding a new type of mitogenic factor. FEBS Lett. 331: 187 192.
62. Iwasaki, M.,, H. Igarashi,, and T. Yutsudo. 1997. Mitogenic factor secreted by Streptococcus pyogenes is a heat-stable nuclease requiring His122 for activity. Microbiology 143: 2449 2455.
63. Jardetzky, T. S.,, J. H. Brown,, J. C. Gorga,, L. J. Stern,, R. G. Urban,, Y. I. Chi,, C. Stauffacher,, J. L. Strominger,, and D. C. Wiley. 1994. Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen. Nature 368: 711 718.
64. Johnson, D. R.,, D. L. Stevens,, and E. L. Kaplan. 1992. Epidemiologic analysis of group A streptococcal serotypes associated with severe systemic infections, rheumatic fever, or uncomplicated pharyngitis. J. Infect. Dis. 166: 374 382.
65. Johnson, L. P.,, and P. M. Schlievert. 1984. Group A streptococcal phage T12 carries the structural gene for pyrogenic exotoxin type A. Mol. Gen. Genet. 194: 52 56.
66. Johnson, L. P.,, and P. M. Schlievert. 1983. A physical map of the group A streptococcal pyrogenic exotoxin bacteriophage T12 genome. Mol. Gen. Genet. 189: 251 255.
67. Kalia, A.,, and D. E. Bessen. 2003. Presence of streptococcal pyrogenic exotoxin A and C genes in human isolates of group G streptococci. FEMS Microbiol. Lett. 219: 291 295.
68. Kansal, R. G.,, A. McGeer,, D. E. Low,, A. Norrby-Teglund,, and M. Kotb. 2000. 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.
69. Kansal, R. G.,, V. Nizet,, A. Jeng,, W. J. Chuang,, and M. Kotb. 2003. Selective modulation of superantigen-induced responses by streptococcal cysteine protease. J. Infect. Dis. 187: 398 407.
70. Kapur, V.,, M. W. Majesky,, L. L. Li,, R. A. Black,, and J. M. Musser. 1993. Cleavage of interleukin 1 beta (IL-1 beta) precursor to produce active IL-1 beta by a conserved extracellular cysteine protease from Streptococcus pyogenes. Proc. Natl. Acad. Sci. USA 90: 7676 7680.
71. Kapur, V.,, S. Topouzis,, M. W. Majesky,, L. L. Li,, M. R. Hamrick,, R. J. Hamill,, J. M. Patti,, and J. M. Musser. 1993. A conserved Streptococcus pyogenes extracellular cysteine protease cleaves human fibronectin and degrades vitronectin. Microb. Pathog. 15: 327 346.
72. Kehoe, M. A.,, L. Miller,, J. A. Walker,, and G. J. Boulnois. 1987. Nucleotide sequence of the streptolysin O (SLO) gene: structural homologies between SLO and other membrane-damaging, thiol-activated toxins. Infect. Immun. 55: 3228 3232.
73. Kim, J.,, R. G. Urban,, J. L. Strominger,, and D. C. Wiley. 1994. Toxic shock syndrome toxin-1 complexed with a class II major histocompatibility molecule HLA-DR1. Science 266: 1870 1874.
74. Kotb, M. 1995. Bacterial pyrogenic exotoxins as superantigens. Clin. Microbiol. Rev. 8: 411 426.
75. Kotb, M.,, A. Norrby-Teglund,, A. McGeer,, H. El-Sherbini,, M. T. Dorak,, A. Khurshid,, K. Green,, J. Peeples,, J. Wade,, G. Thomson,, B. Schwartz,, and D. E. Low. 2002. An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nat. Med. 8: 1398 1404.
76. Leonard, B. A.,, P. K. Lee,, M. K. Jenkins,, and P. M. Schlievert. 1991. Cell and receptor requirements for streptococcal pyrogenic exotoxin T-cell mitogenicity. Infect. Immun. 59: 1210 1214.
77. Li, H.,, A. Llera,, E. L. Malchiodi,, and R. A. Mariuzza. 1999. The structural basis of T cell activation by superantigens. Annu. Rev. Immunol. 17: 435 466.
78. Li, H.,, A. Llera,, D. Tsuchiya,, L. Leder,, X. Ysern,, P. M. Schlievert,, K. Karjalainen,, and R. A. Mariuzza. 1998. Three-dimensional structure of the complex between a T cell receptor beta chain and the superantigen staphylococcal enterotoxin B. Immunity 9: 807 816.
79. Li, P. L.,, R. E. Tiedemann,, S. L. Moffat,, and J. D. Fraser. 1997. The superantigen streptococcal pyrogenic exotoxin C (SPE-C) exhibits a novel mode of action. J. Exp. Med. 186: 375 383.
80. Li, Y.,, H. Li,, N. Dimasi,, J. K. McCormick,, R. Martin,, P. Schuck,, P. M. Schlievert,, and R. A. Mariuzza. 2001. Crystal structure of a superantigen bound to the high-affinity, zinc-dependent site on MHC class II. Immunity 14: 93 104.
81. Llewelyn, M.,, S. Sriskandan,, M. Peakman,, D. R. Ambrozak,, D. C. Douek,, W. W. Kwok,, J. Cohen,, and D. M. Altmann. 2004. HLA class II polymorphisms determine responses to bacterial superantigens. J. Immunol. 172: 1719 1726.
82. Lukomski, S.,, E. H. Burns, Jr.,, P. R. Wyde,, A. Podbielski,, J. Rurangirwa,, D. K. Moore-Poveda,, and J. M. Musser. 1998. 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.
83. Lukomski, S.,, N. P. Hoe,, I. Abdi,, J. Rurangirwa,, P. Kordari,, M. Liu,, S. J. Dou,, G. G. Adams,, and J. M. Musser. 2000. Nonpolar inactivation of the hypervariable streptococcal inhibitor of complement gene (sic) in serotype M1 Streptococcus pyogenes significantly decreases mouse mucosal colonization. Infect. Immun. 68: 535 542.
84. Marrack, P.,, and J. Kappler. 1990. The staphylococcal enterotoxins and their relatives. Science 248: 705 711.
85. Massell, B. F.,, C. G. Chute,, A. M. Walker,, and G. S. Kurland. 1988. Penicillin and the marked decrease in morbidity and mortality from rheumatic fever in the United States. N. Engl. J. Med. 318: 280 286.
86. Matsuka, Y. V.,, S. Pillai,, S. Gubba,, J. M. Musser,, and S. B. Olmsted. 1999. Fibrinogen cleavage by the Streptococcus pyogenes extracellular cysteine protease and generation of antibodies that inhibit enzyme proteolytic activity. Infect. Immun. 67: 4326 4333.
87. McCormick, J. K.,, A. A. Pragman,, J. C. Stolpa,, D. Y. Leung,, and P. M. Schlievert. 2001. Functional characterization of streptococcal pyrogenic exotoxin J, a novel superantigen. Infect. Immun. 69: 1381 1388.
88. McCormick, J. K.,, and P. M. Schlievert. 2003. Expression, purification, and detection of novel streptococcal superantigens. Methods Mol. Biol. 214: 33 43.
89. McCormick, J. K.,, T. J. Tripp,, A. S. Llera,, E. J. Sundberg,, M. M. Dinges,, R. A. Mariuzza,, and P. M. Schlievert. 2003. Functional analysis of the TCR binding domain of toxic shock syndrome toxin-1 predicts further diversity in MHC class II/superantigen/TCR ternary complexes. J. Immunol. 171: 1385 1392.
90. McCormick, J. K.,, T. J. Tripp,, S. B. Olmsted,, Y. V. Matsuka,, P. J. Gahr,, D. H. Ohlendorf,, and P. M. Schlievert. 2000. Development of streptococcal pyrogenic exotoxin C vaccine toxoids that are protective in the rabbit model of toxic shock syndrome. J. Immunol. 165: 2306 2312.
91. McCormick, J. K.,, J. M. Yarwood,, and P. M. Schlievert. 2001. Toxic shock syndrome and bacterial superantigens: an update. Annu. Rev. Microbiol. 55: 77 104.
92. McShan, W. M.,, Y. F. Tang,, and J. J. Ferretti. 1997. Bacteriophage T12 of Streptococcus pyogenes integrates into the gene encoding a serine tRNA. Mol. Microbiol. 23: 719 728.
93. Mitchell, D. T.,, D. G. Levitt,, P. M. Schlievert,, and D. H. Ohlendorf. 2000. Structural evidence for the evolution of pyrogenic toxin superantigens. J. Mol. Evol. 51: 520 531.
94. Miyoshi-Akiyama, T.,, J. Zhao,, H. Kato,, K. Kikuchi,, K. Totsuka,, Y. Kataoka,, M. Katsumi,, and T. Uchiyama. 2003. Streptococcus dysgalactiae-derived mitogen (SDM), a novel bacterial superantigen: characterization of its biological activity and predicted tertiary structure. Mol. Microbiol. 47: 1589 1599.
95. Muller-Alouf, H.,, D. Gerlach,, P. Desreumaux,, C. Leportier,, J. E. Alouf,, and M. Capron. 1997. Streptococcal pyrogenic exotoxin A (SPE A) superantigen induced production of hematopoietic cytokines, IL-12 and IL-13 by human peripheral blood mononuclear cells. Microb. Pathog. 23: 265 272.
96. Musser, J. M.,, A. R. Hauser,, M. H. Kim,, P. M. Schlievert,, K. Nelson,, and R. K. Selander. 1991. Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression. Proc. Natl. Acad. Sci. USA 88: 2668 2672.
97. Musser, J. M.,, V. Kapur,, J. Szeto,, X. Pan,, D. S. Swanson,, and D. R. Martin. 1995. Genetic diversity and relationships among Streptococcus pyogenes strains expressing serotype M1 protein: recent intercontinental spread of a subclone causing episodes of invasive disease. Infect. Immun. 63: 994 1003.
98. Nakagawa, I.,, K. Kurokawa,, A. Yamashita,, M. Nakata,, Y. Tomiyasu,, N. Okahashi,, S. Kawabata,, K. Yamazaki,, T. Shiba,, T. Yasunaga,, H. Hayashi,, M. Hattori,, and S. Hamada. 2003. 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.
99. Nelson, K.,, P. M. Schlievert,, R. K. Selander,, and J. M. Musser. 1991. Characterization and clonal distribution of four alleles of the speA gene encoding pyrogenic exotoxin A (scarlet fever toxin) in Streptococcus pyogenes. J. Exp. Med. 174: 1271 1274.
100. Newton, D.,, A. Norrby-Teglund,, A. McGeer,, D. E. Low,, P. M. Schlievert,, and M. Kotb. 1997. Novel superantigens from streptococcal toxic shock syndrome Streptococcus pyogenes isolates. Adv. Exp. Med. Biol. 418: 525 529.
101. Nizet, V.,, B. Beall,, D. J. Bast,, V. Datta,, L. Kilburn,, D. E. Low,, and J. C. De Azavedo. 2000. Genetic locus for streptolysin S production by group A streptococcus. Infect. Immun. 68: 4245 4254.
102. Norrby-Teglund, A.,, D. Newton,, M. Kotb,, S. E. Holm,, and M. Norgren. 1994. Superantigenic properties of the group A streptococcal exotoxin SpeF (MF). Infect. Immun. 62: 5227 5233.
103. Nyberg, P.,, M. Rasmussen,, U. Von Pawel-Rammingen,, and L. Bjorck. 2004. SpeB modulates fibronectin-dependent internalization of Streptococcus pyogenes by efficient proteolysis of cell-wall-anchored protein F1. Microbiology 150: 1559 1569.
104. Ohkuni, H.,, Y. Todome,, Y. Watanabe,, T. Ishikaw,, H. Takahashi,, Y. Kannari,, H. Kato,, T. Uchiyama,, H. Saito,, V. A. Fischetti,, and J. B. Zabriskie. 2004. Studies of recombinant streptococcal pyrogenic exotoxin B/cysteine protease (rSPE B/SCP) in the skin of guinea pigs and the release of histamine from cultured mast cells and basophilic leukocytes. Indian J. Med. Res. 119(Suppl.): 33 36.
105. Palmer, M.,, A. Valeva,, M. Kehoe,, and S. Bhakdi. 1995. Kinetics of streptolysin O self-assembly. Eur. J. Biochem. 231: 388 395.
106. Parsonnet, J.,, Z. A. Gillis,, A. G. Richter,, and G. B. Pier. 1987. A rabbit model of toxic shock syndrome that uses a constant, subcutaneous infusion of toxic shock syndrome toxin 1. Infect. Immun. 55: 1070 1076.
107. Parsonnet, J.,, R. K. Hickman,, D. D. Eardley,, and G. B. Pier. 1985. Induction of human interleukin-1 by toxic-shock-syndrome toxin-1. J. Infect. Dis. 151: 514 522.
108. Petersson, K.,, M. Hakansson,, H. Nilsson,, G. Forsberg,, L. A. Svensson,, A. Liljas,, and B. Walse. 2001. Crystal structure of a superantigen bound to MHC class II displays zinc and peptide dependence. EMBO J. 20: 3306 3312.
109. Petersson, K.,, M. Thunnissen,, G. Forsberg,, and B. Walse. 2002. Crystal structure of a SEA variant in complex with MHC class II reveals the ability of SEA to crosslink MHC molecules. Structure (Camb.) 10: 1619 1626.
110. Proft, T.,, and J. D. Fraser. 2003. Bacterial superantigens. Clin. Exp. Immunol. 133: 299 306.
111. Proft, T.,, S. L. Moffatt,, K. D. Weller,, A. Paterson,, D. Martin,, and J. D. Fraser. 2000. The streptococcal superantigen SMEZ exhibits wide allelic variation, mosaic structure, and significant antigenic variation. J. Exp. Med. 191: 1765 1776.
112. Proft, T.,, P. D. Webb,, V. Handley,, and J. D. Fraser. 2003. Two novel superantigens found in both group A and group C Streptococcus. Infect. Immun. 71: 1361 1369.
113. Rasmussen, M.,, and L. Bjorck. 2002. Proteolysis and its regulation at the surface of Streptococcus pyogenes. Mol. Microbiol. 43: 537 544.
114. Roggiani, M.,, J. A. Stoehr,, S. B. Olmsted,, Y. V. Matsuka,, S. Pillai,, D. H. Ohlendorf,, and P. M. Schlievert. 2000. Toxoids of streptococcal pyrogenic exotoxin A are protective in rabbit models of streptococcal toxic shock syndrome. Infect. Immun. 68: 5011 5017.
115. Roussel, A.,, B. F. Anderson,, H. M. Baker,, J. D. Fraser,, and E. N. Baker. 1997. Crystal structure of the streptococcal superantigen SPE-C: dimerization and zinc binding suggest a novel mode of interaction with MHC class II molecules. Nat. Struct. Biol. 4: 635 643.
116. Ruiz, N.,, B. Wang,, A. Pentland,, and M. Caparon. 1998. Streptolysin O and adherence synergistically modulate proinflammatory responses of keratinocytes to group A streptococci. Mol. Microbiol. 27: 337 346.
117. Sachse, S.,, P. Seidel,, D. Gerlach,, E. Gunther,, J. Rodel,, E. Straube,, and K. H. Schmidt. 2002. Superantigen-like gene(s) in human pathogenic Streptococcus dysgalactiae, subsp equisimilis: genomic localisation of the gene encoding streptococcal pyrogenic exotoxin G ( speG dys). FEMS Immunol. Med. Microbiol. 34: 159 167.
118. Schlievert, P. M.,, A. P. Assimacopoulos,, and P. P. Cleary. 1996. Severe invasive group A streptococcal disease: clinical description and mechanisms of pathogenesis. J. Lab. Clin. Med. 127: 13 22.
119. Schlievert, P. M.,, K. M. Bettin,, and D. W. Watson. 1979. Production of pyrogenic exotoxin by groups of streptococci: association with group A. J. Infect. Dis. 140: 676 681.
120. Schlievert, P. M.,, K. M. Bettin,, and D. W. Watson. 1979. Reinterpretation of the Dick test: role of group A streptococcal pyrogenic exotoxin. Infect. Immun. 26: 467 472.
121. Smoot, J. C.,, K. D. Barbian,, J. J. Van Gompel,, L. M. Smoot,, M. S. Chaussee,, G. L. Sylva,, D. E. Sturdevant,, S. M. Ricklefs,, S. F. Porcella,, L. D. Parkins,, S. B. Beres,, D. S. Campbell,, T. M. Smith,, Q. Zhang,, V. Kapur,, J. A. Daly,, L. G. Veasy,, and J. M. Musser. 2002. 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.
122. Sriskandan, S.,, D. Moyes,, and J. Cohen. 1996. Detection of circulating bacterial superantigen and lymphotoxin-alpha in patients with streptococcal toxic-shock syndrome. Lancet 348: 1315 136.
123. Sriskandan, S.,, M. Unnikrishnan,, T. Krausz,, and J. Cohen. 1999. Molecular analysis of the role of streptococcal pyrogenic exotoxin A (SPEA) in invasive soft-tissue infection resulting from Streptococcus pyogenes. Mol. Microbiol. 33: 778 790.
124. Stevens, D. L.,, M. H. Tanner,, J. Winship,, R. Swarts,, K. M. Ries,, P. M. Schlievert,, and E. Kaplan. 1989. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N. Engl. J. Med. 321: 1 7.
125. Sundberg, E.,, and T. S. Jardetzky. 1999. Structural basis for HLA-DQ binding by the streptococcal superantigen SSA. Nat. Struct. Biol. 6: 123 129.
126. Sundberg, E. J.,, P. S. Andersen,, P. M. Schlievert,, K. Karjalainen,, and R. A. Mariuzza. 2003. Structural, energetic, and functional analysis of a protein-protein interface at distinct stages of affinity maturation. Structure (Camb.) 11: 1151 1161.
127. Sundberg, E. J.,, H. Li,, A. S. Llera,, J. K. McCormick,, J. Tormo,, P. M. Schlievert,, K. Karjalainen,, and R. A. Mariuzza. 2002. Structures of two streptococcal superantigens bound to TCR beta chains reveal diversity in the architecture of T cell signaling complexes. Structure (Camb.) 10: 687 699.
128. Sundberg, E. J.,, Y. Li,, and R. A. Mariuzza. 2002. So many ways of getting in the way: diversity in the molecular architecture of superantigen-dependent T-cell signaling complexes. Curr. Opin. Immunol. 14: 36 44.
129. Svensson, M. D.,, D. A. Scaramuzzino,, U. Sjobring,, A. Olsen,, C. Frank,, and D. E. Bessen. 2000. Role for a secreted cysteine proteinase in the establishment of host tissue tropism by group A streptococci. Mol. Microbiol. 38: 242 253.
130. Swietnicki, W.,, A. M. Barnie,, B. K. Dyas,, and R. G. Ulrich. 2003. Zinc binding and dimerization of Streptococcus pyogenes pyrogenic exotoxin C are not essential for T-cell stimulation. J. Biol. Chem. 278: 9885 9895.
131. Tomai, M. A.,, P. M. Schlievert,, and M. Kotb. 1992. Distinct T-cell receptor V beta gene usage by human T lymphocytes stimulated with the streptococcal pyrogenic exotoxins and pep M5 protein. Infect. Immun. 60: 701 705.
132. Tripp, T. J.,, J. K. McCormick,, J. M. Webb,, and P. M. Schlievert. 2003. The zinc-dependent major histocompatibility complex class II binding site of streptococcal pyrogenic exotoxin C is critical for maximal superantigen function and toxic activity. Infect. Immun. 71: 1548 1550.
133. Unnikrishnan, M.,, J. Cohen,, and S. Sriskandan. 2001. Complementation of a speA negative Streptococcus pyogenes with speA: effects on virulence and production of streptococcal pyrogenic exotoxin A. Microb. Pathog. 31: 109 114.
134. Watson, D. W. 1960. Host-parasite factors in group A streptococcal infections. Pyrogenic and other effects of immunologic distinct exotoxins related to scarlet fever toxins. J. Exp. Med. 111: 255 284.
135. Weeks, C. R.,, and J. J. Ferretti. 1986. Nucleotide sequence of the type A streptococcal exotoxin (erythrogenic toxin) gene from Streptococcus pyogenes bacteriophage T12. Infect. Immun. 52: 144 150.
136. White, J.,, A. Herman,, A. M. Pullen,, R. Kubo,, J. W. Kappler,, and P. Marrack. 1989. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell 56: 27 35.
137. Yu, C. E.,, and J. J. Ferretti. 1991. Frequency of the erythrogenic toxin B and C genes (speB and speC) among clinical isolates of group A streptococci. Infect. Immun. 59: 211 215.
138. Yutsudo, T.,, H. Murai,, J. Gonzalez,, T. Takao,, Y. Shimonishi,, Y. Takeda,, H. Igarashi,, and Y. Hinuma. 1992. A new type of mitogenic factor produced by Streptococcus pyogenes. FEBS Lett. 308: 30 34.
139. Yutsudo, T.,, K. Okumura,, M. Iwasaki,, A. Hara,, S. Kamitani,, W. Minamide,, H. Igarashi,, and Y. Hinuma. 1994. The gene encoding a new mitogenic factor in a Streptococcus pyogenes strain is distributed only in group A streptococci. Infect. Immun. 62: 4000 4004.
140. Zabriskie, J. B. 1964. The role of temperate bacteriophage in the production of erythrogenic toxin by group A streptococci. J. Exp. Med. 119: 761 780.

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