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. 1994 May;62(5):1867–1874. doi: 10.1128/iai.62.5.1867-1874.1994

Molecular characterization and phylogenetic distribution of the streptococcal superantigen gene (ssa) from Streptococcus pyogenes.

K B Reda 1, V Kapur 1, J A Mollick 1, J G Lamphear 1, J M Musser 1, R R Rich 1
PMCID: PMC186429  PMID: 8168951

Abstract

A striking increase in the frequency and severity of invasive infections caused by Streptococcus pyogenes has occurred in recent years. Among these diseases is streptococcal toxic-shock-like syndrome (TSLS), a condition characterized by fulminant soft-tissue destruction and multiorgan failure. Streptococcal superantigen (SSA), a superantigen isolated from a TSLS-inducing, serotype M3 S. pyogenes strain, has recently been identified. We here describe the cloning, sequencing, and phylogenetic distribution of the SSA structural gene. The 783-bp open reading frame encodes a predicted 260-amino-acid protein that is similar in size to several other bacterial superantigens. The deduced sequence of the mature protein is 60.2% identical to that of staphylococcal enterotoxin B but only 49% identical to that of streptococcal pyrogenic exotoxin A. Southern blot and PCR analysis of 138 group A streptococcal strains representing 65 M protein serotypes and 15 nontypeable isolates identified ssa in 68 strains from 10 distinct clonal lineages. All ssa-positive clones expressed SSA. Of the two clones associated with TSLS, the ET 2-M3 lineage, but not the ET 1-M1 lineage, carried the SSA gene. Further analysis of the ET 2-M3 lineage found evidence for temporal variation in ssa association. Contemporary ET 2-M3 disease isolates had ssa, but two older isolates of this clone recovered in 1910 and 1920 lacked the gene. The clonal and temporal distribution patterns of ssa suggest a relatively recent acquisition of this superantigen-encoding gene by the ET 2-M3 lineage, perhaps by horizontal transfer and recombination.

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  1. Abe J., Kotzin B. L., Jujo K., Melish M. E., Glode M. P., Kohsaka T., Leung D. Y. Selective expansion of T cells expressing T-cell receptor variable regions V beta 2 and V beta 8 in Kawasaki disease. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4066–4070. doi: 10.1073/pnas.89.9.4066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bayles K. W., Iandolo J. J. Genetic and molecular analyses of the gene encoding staphylococcal enterotoxin D. J Bacteriol. 1989 Sep;171(9):4799–4806. doi: 10.1128/jb.171.9.4799-4806.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Betley M. J., Borst D. W., Regassa L. B. Staphylococcal enterotoxins, toxic shock syndrome toxin and streptococcal pyrogenic exotoxins: a comparative study of their molecular biology. Chem Immunol. 1992;55:1–35. [PubMed] [Google Scholar]
  4. Betley M. J., Mekalanos J. J. Nucleotide sequence of the type A staphylococcal enterotoxin gene. J Bacteriol. 1988 Jan;170(1):34–41. doi: 10.1128/jb.170.1.34-41.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Betley M. J., Mekalanos J. J. Staphylococcal enterotoxin A is encoded by phage. Science. 1985 Jul 12;229(4709):185–187. doi: 10.1126/science.3160112. [DOI] [PubMed] [Google Scholar]
  6. Bisno A. L. Group A streptococcal infections and acute rheumatic fever. N Engl J Med. 1991 Sep 12;325(11):783–793. doi: 10.1056/NEJM199109123251106. [DOI] [PubMed] [Google Scholar]
  7. Blomster-Hautamaa D. A., Kreiswirth B. N., Kornblum J. S., Novick R. P., Schlievert P. M. The nucleotide and partial amino acid sequence of toxic shock syndrome toxin-1. J Biol Chem. 1986 Nov 25;261(33):15783–15786. [PubMed] [Google Scholar]
  8. Bohach G. A., Schlievert P. M. Conservation of the biologically active portions of staphylococcal enterotoxins C1 and C2. Infect Immun. 1989 Jul;57(7):2249–2252. doi: 10.1128/iai.57.7.2249-2252.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bohach G. A., Schlievert P. M. Nucleotide sequence of the staphylococcal enterotoxin C1 gene and relatedness to other pyrogenic toxins. Mol Gen Genet. 1987 Aug;209(1):15–20. doi: 10.1007/BF00329830. [DOI] [PubMed] [Google Scholar]
  10. Cardell S., Höidén I., Möller G. Manipulation of the superantigen-induced lymphokine response. Selective induction of interleukin-10 or interferon-gamma synthesis in small resting CD4+ T cells. Eur J Immunol. 1993 Feb;23(2):523–529. doi: 10.1002/eji.1830230234. [DOI] [PubMed] [Google Scholar]
  11. Choi Y., Lafferty J. A., Clements J. R., Todd J. K., Gelfand E. W., Kappler J., Marrack P., Kotzin B. L. Selective expansion of T cells expressing V beta 2 in toxic shock syndrome. J Exp Med. 1990 Sep 1;172(3):981–984. doi: 10.1084/jem.172.3.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Couch J. L., Soltis M. T., Betley M. J. Cloning and nucleotide sequence of the type E staphylococcal enterotoxin gene. J Bacteriol. 1988 Jul;170(7):2954–2960. doi: 10.1128/jb.170.7.2954-2960.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Drake C. G., Kotzin B. L. Superantigens: biology, immunology, and potential role in disease. J Clin Immunol. 1992 May;12(3):149–162. doi: 10.1007/BF00918083. [DOI] [PubMed] [Google Scholar]
  14. Felsenstein J. Phylogenies from molecular sequences: inference and reliability. Annu Rev Genet. 1988;22:521–565. doi: 10.1146/annurev.ge.22.120188.002513. [DOI] [PubMed] [Google Scholar]
  15. Firestein G. S. Mechanisms of tissue destruction and cellular activation in rheumatoid arthritis. Curr Opin Rheumatol. 1992 Jun;4(3):348–354. doi: 10.1097/00002281-199206000-00012. [DOI] [PubMed] [Google Scholar]
  16. Goshorn S. C., Schlievert P. M. Bacteriophage association of streptococcal pyrogenic exotoxin type C. J Bacteriol. 1989 Jun;171(6):3068–3073. doi: 10.1128/jb.171.6.3068-3073.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goshorn S. C., Schlievert P. M. Nucleotide sequence of streptococcal pyrogenic exotoxin type C. Infect Immun. 1988 Sep;56(9):2518–2520. doi: 10.1128/iai.56.9.2518-2520.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gray E. D., Wannamaker L. W., Ayoub E. M., el Kholy A., Abdin Z. H. Cellular immune responses to extracellular streptococcal products in rheumatic heart disease. J Clin Invest. 1981 Sep;68(3):665–671. doi: 10.1172/JCI110301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Grossman D., Van M., Mollick J. A., Highlander S. K., Rich R. R. Mutation of the disulfide loop in staphylococcal enterotoxin A. Consequences for T cell recognition. J Immunol. 1991 Nov 15;147(10):3274–3281. [PubMed] [Google Scholar]
  20. Hackett S. P., Stevens D. L. Streptococcal toxic shock syndrome: synthesis of tumor necrosis factor and interleukin-1 by monocytes stimulated with pyrogenic exotoxin A and streptolysin O. J Infect Dis. 1992 May;165(5):879–885. doi: 10.1093/infdis/165.5.879. [DOI] [PubMed] [Google Scholar]
  21. Hauser A. R., Stevens D. L., Kaplan E. L., Schlievert P. M. Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome. J Clin Microbiol. 1991 Aug;29(8):1562–1567. doi: 10.1128/jcm.29.8.1562-1567.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Higgins D. G., Sharp P. M. CLUSTAL: a package for performing multiple sequence alignment on a microcomputer. Gene. 1988 Dec 15;73(1):237–244. doi: 10.1016/0378-1119(88)90330-7. [DOI] [PubMed] [Google Scholar]
  23. Hoge C. W., Schwartz B., Talkington D. F., Breiman R. F., MacNeill E. M., Englender S. J. The changing epidemiology of invasive group A streptococcal infections and the emergence of streptococcal toxic shock-like syndrome. A retrospective population-based study. JAMA. 1993 Jan 20;269(3):384–389. [PubMed] [Google Scholar]
  24. Holm S. E., Norrby A., Bergholm A. M., Norgren M. Aspects of pathogenesis of serious group A streptococcal infections in Sweden, 1988-1989. J Infect Dis. 1992 Jul;166(1):31–37. doi: 10.1093/infdis/166.1.31. [DOI] [PubMed] [Google Scholar]
  25. Hudson K. R., Robinson H., Fraser J. D. Two adjacent residues in staphylococcal enterotoxins A and E determine T cell receptor V beta specificity. J Exp Med. 1993 Jan 1;177(1):175–184. doi: 10.1084/jem.177.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Irwin M. J., Hudson K. R., Fraser J. D., Gascoigne N. R. Enterotoxin residues determining T-cell receptor V beta binding specificity. Nature. 1992 Oct 29;359(6398):841–843. doi: 10.1038/359841a0. [DOI] [PubMed] [Google Scholar]
  27. Jones C. L., Khan S. A. Nucleotide sequence of the enterotoxin B gene from Staphylococcus aureus. J Bacteriol. 1986 Apr;166(1):29–33. doi: 10.1128/jb.166.1.29-33.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kaplan E. L., Johnson D. R., Cleary P. P. Group A streptococcal serotypes isolated from patients and sibling contacts during the resurgence of rheumatic fever in the United States in the mid-1980s. J Infect Dis. 1989 Jan;159(1):101–103. doi: 10.1093/infdis/159.1.101. [DOI] [PubMed] [Google Scholar]
  29. Kappler J. W., Herman A., Clements J., Marrack P. Mutations defining functional regions of the superantigen staphylococcal enterotoxin B. J Exp Med. 1992 Feb 1;175(2):387–396. doi: 10.1084/jem.175.2.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kappler J., Kotzin B., Herron L., Gelfand E. W., Bigler R. D., Boylston A., Carrel S., Posnett D. N., Choi Y., Marrack P. V beta-specific stimulation of human T cells by staphylococcal toxins. Science. 1989 May 19;244(4906):811–813. doi: 10.1126/science.2524876. [DOI] [PubMed] [Google Scholar]
  31. Kapur V., Nelson K., Schlievert P. M., Selander R. K., Musser J. M. Molecular population genetic evidence of horizontal spread of two alleles of the pyrogenic exotoxin C gene (speC) among pathogenic clones of Streptococcus pyogenes. Infect Immun. 1992 Sep;60(9):3513–3517. doi: 10.1128/iai.60.9.3513-3517.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Leung D. Y. Kawasaki disease. Curr Opin Rheumatol. 1993 Jan;5(1):41–50. doi: 10.1097/00002281-199305010-00007. [DOI] [PubMed] [Google Scholar]
  33. Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
  34. Miethke T., Wahl C., Heeg K., Echtenacher B., Krammer P. H., Wagner H. T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumor necrosis factor. J Exp Med. 1992 Jan 1;175(1):91–98. doi: 10.1084/jem.175.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mollick J. A., Cook R. G., Rich R. R. Class II MHC molecules are specific receptors for staphylococcus enterotoxin A. Science. 1989 May 19;244(4906):817–820. doi: 10.1126/science.2658055. [DOI] [PubMed] [Google Scholar]
  36. Mollick J. A., McMasters R. L., Grossman D., Rich R. R. Localization of a site on bacterial superantigens that determines T cell receptor beta chain specificity. J Exp Med. 1993 Feb 1;177(2):283–293. doi: 10.1084/jem.177.2.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mollick J. A., Miller G. G., Musser J. M., Cook R. G., Grossman D., Rich R. R. A novel superantigen isolated from pathogenic strains of Streptococcus pyogenes with aminoterminal homology to staphylococcal enterotoxins B and C. J Clin Invest. 1993 Aug;92(2):710–719. doi: 10.1172/JCI116641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Musser J. M., Hauser A. R., Kim M. H., Schlievert P. M., Nelson K., Selander R. K. Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2668–2672. doi: 10.1073/pnas.88.7.2668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Musser J. M., Kapur V., Kanjilal S., Shah U., Musher D. M., Barg N. L., Johnston K. H., Schlievert P. M., Henrichsen J., Gerlach D. Geographic and temporal distribution and molecular characterization of two highly pathogenic clones of Streptococcus pyogenes expressing allelic variants of pyrogenic exotoxin A (Scarlet fever toxin). J Infect Dis. 1993 Feb;167(2):337–346. doi: 10.1093/infdis/167.2.337. [DOI] [PubMed] [Google Scholar]
  40. Musser J. M., Nelson K., Selander R. K., Gerlach D., Huang J. C., Kapur V., Kanjilal S. Temporal variation in bacterial disease frequency: molecular population genetic analysis of scarlet fever epidemics in Ottawa and in eastern Germany. J Infect Dis. 1993 Mar;167(3):759–762. doi: 10.1093/infdis/167.3.759. [DOI] [PubMed] [Google Scholar]
  41. Ohga S., Okada K., Mitsui K., Aoki T., Ueda K. Outbreaks of group A beta-hemolytic streptococcal pharyngitis in children: correlation of serotype T4 with scarlet fever. Scand J Infect Dis. 1992;24(5):599–605. doi: 10.3109/00365549209054645. [DOI] [PubMed] [Google Scholar]
  42. Paliard X., West S. G., Lafferty J. A., Clements J. R., Kappler J. W., Marrack P., Kotzin B. L. Evidence for the effects of a superantigen in rheumatoid arthritis. Science. 1991 Jul 19;253(5017):325–329. doi: 10.1126/science.1857971. [DOI] [PubMed] [Google Scholar]
  43. Rosenberg M., Court D. Regulatory sequences involved in the promotion and termination of RNA transcription. Annu Rev Genet. 1979;13:319–353. doi: 10.1146/annurev.ge.13.120179.001535. [DOI] [PubMed] [Google Scholar]
  44. Schwartz B., Facklam R. R., Breiman R. F. Changing epidemiology of group A streptococcal infection in the USA. Lancet. 1990 Nov 10;336(8724):1167–1171. doi: 10.1016/0140-6736(90)92777-f. [DOI] [PubMed] [Google Scholar]
  45. Selander R. K., Caugant D. A., Ochman H., Musser J. M., Gilmour M. N., Whittam T. S. Methods of multilocus enzyme electrophoresis for bacterial population genetics and systematics. Appl Environ Microbiol. 1986 May;51(5):873–884. doi: 10.1128/aem.51.5.873-884.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Shine J., Dalgarno L. The 3'-terminal sequence of Escherichia coli 16S ribosomal RNA: complementarity to nonsense triplets and ribosome binding sites. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1342–1346. doi: 10.1073/pnas.71.4.1342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Stevens D. L., Tanner M. H., Winship J., Swarts R., Ries K. M., Schlievert P. M., Kaplan E. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med. 1989 Jul 6;321(1):1–7. doi: 10.1056/NEJM198907063210101. [DOI] [PubMed] [Google Scholar]
  48. Swaminathan S., Furey W., Pletcher J., Sax M. Crystal structure of staphylococcal enterotoxin B, a superantigen. Nature. 1992 Oct 29;359(6398):801–806. doi: 10.1038/359801a0. [DOI] [PubMed] [Google Scholar]
  49. Talkington D. F., Schwartz B., Black C. M., Todd J. K., Elliott J., Breiman R. F., Facklam R. R. Association of phenotypic and genotypic characteristics of invasive Streptococcus pyogenes isolates with clinical components of streptococcal toxic shock syndrome. Infect Immun. 1993 Aug;61(8):3369–3374. doi: 10.1128/iai.61.8.3369-3374.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Weeks C. R., Ferretti J. J. The gene for type A streptococcal exotoxin (erythrogenic toxin) is located in bacteriophage T12. Infect Immun. 1984 Nov;46(2):531–536. doi: 10.1128/iai.46.2.531-536.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]

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