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Superantigens and pseudosuperantigens of gram-positive cocci

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Abstract

Superantigens use an elaborate and unique mechanism of T lymphocyte stimulation. Prototype superantigen are the pyrogenic exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes. Many candidate proteins of bacterial, viral and protozoal origin have recently been reported to be superantigens. In most cases the evidence that these proteins are in fact superantigens is highly indirect. In this review the evidence that grampositive cocci produce superantigens other than the pyrogenic exotoxins is critically discussed. Evidence in described demonstrating that the epidermolytic toxins of Staphylococcus aureus and the pyrogenic exotoxin B and M-proteins of Streptococcus pyrogenes are not superantigens. Criteria are described for acceptance of a candidate as a superantigen.

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References

  1. Fleischer B, Schrezenmeier H (1988) T cell Stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for MHC class II molecules on accessory or target cells. J Exp Med 167: 1697–1708

    Google Scholar 

  2. Janeway CA Jr (1991) Selective elements for the V β region of the T cell receptor: Mls and the bacterial toxic mitogens. Adv Immunol 50: 1–53

    Google Scholar 

  3. White J, Herman A, Pullen AM, Kubo R, Kappler JW, Marrack P (1989) The Vβ-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell 56: 27–35

    Google Scholar 

  4. Held W, Acha-Orbea H, MacDonald HR, Waanders GA (1994) Superantigens and retroviral infection: insights from mouse mammary tumor virus. Immunol Today 15: 184–190

    Google Scholar 

  5. Marrack P, Winslow GM, Choi Y, Scherer M, Pullen A, White J, Kappler JW (1993) The bacterial and mouse mammary tumor virus superantigens; two different families of proteins with the same functions. Immunol Rev 131: 79–92

    Google Scholar 

  6. Matthes M, Schrezenmeier H, Homfeld J, Fleischer S, Malissen B, Kirchner H, Fleischer B (1988) Clonal analysis of human T cell activation by the mycoplasma arthritidis mitogen. Eur J Immunol 18: 1733–1737

    Google Scholar 

  7. Cole BC, Atkin CL (1991) The Mycoplasma arthritidis T cell mitogen MAM: a model superantigen. Immunol Today 12: 271–276

    Google Scholar 

  8. McClane BA (1994) Clostridium perfringens enterotoxin acts by producing small molecule permeability alterations in plasma membranes. Toxicology 87: 43–67

    Google Scholar 

  9. Lee PK, Schlievert PM (1991) Molecular genetics of pyrogenic exotoxin “superantigen” of group A streptococci and Staphylococcus aureus. Curr Top Microbiol Immunol 174: 1–20

    Google Scholar 

  10. Betley MJ, Borst DW, Regassa LB (1992) Staphylococcal enterotoxins, toxic shock syndrome toxin and streptococcal pyrogenic exotoxins: a comparative study of their molecular biology. Chem Immunol 55: 1–35

    Google Scholar 

  11. Marrack P, Kappler JW (1990) The staphylococcal enterotoxins and their relatives. Science 248: 705–711

    Google Scholar 

  12. Reda KB, Kapur V, Mollick JA, Lamphear JG, Musser JM, Rich RR (1994) Molecular characterization and phylogenetic distribution of the streptococcal superantigen gene (ssa) from Streptococcus pyogenes. Infect Immun 62: 1867–1874

    Google Scholar 

  13. Fleischer B (1995) Bacterial superantigens. Rev Med Microbiol 6: (in press)

  14. Bergdoll MS (1983) Enterotoxins. In: Easmon SCF, Adlams C (eds) Staphylococci and staphylococcal infections. Academic Press, New York, pp 559–598

    Google Scholar 

  15. Musser JM, Schlievert PM, Chow AW, Ewan P, Kreiswirth BN, Rosdahl VT, Naidu AS, Witte W, Selander RK (1990) A single clone of Staphylococcus aureus causes the majority of cases of toxic shock syndrome. Proc Natl Acad Sci USA 87: 225–229

    Google Scholar 

  16. Marr JC, Lyon JD, Roberson JR, Lupher M, Davis WC, Bohach GA (1993) Characterization of novel type C staphylococcal enterotoxins: biological and evolutionary implications. Infect Immun 61: 4254–4262

    Google Scholar 

  17. Fleischer B, Gerardy-Schahn R, Metzroth B, Carrel S, Gerlach D, Köhler W (1991) A conserved mechanism of T cell stimulation by microbial toxins. Evidence for different affinities of T cell receptor-toxin interaction. J Immunol 146: 11–17

    Google Scholar 

  18. Lee PK, Kreiswirth BN, Deringer JR, Projan SJ, Eisner W, Smith BL, Carlson E, Novick RP, Schlievert PM (1992) Nucleotide sequences and biologic properties of toxic shock syndrome toxin 1 from ovine-and bovine-associated Staphylococcus aureus. J Infect Dis 165: 1056–1063

    Google Scholar 

  19. Fleming S, Iandolo J, Chapes S (1991) Murine macrophage activation by staphylococcal exotoxins. Infect Immun 59: 4049–4055

    Google Scholar 

  20. Chapes S, Hoynowski SM, Woods KM, Armstrong JW, Beharka AA, Iandolo JJ (1994) Staphylococcus-mediated T-cell activation and spontaneous natural killer cell activity in the absence of major histocompatibility complex class II molecules. Infect Immun 61: 4013–4016

    Google Scholar 

  21. Leonard BA, Lee PK, Jenkins MK, Schlievert PM (1991) Cell and receptor requirements for streptococcal pyrogenic exotoxin T cell mitogenicity. Infect Immun 59: 1210–1214

    Google Scholar 

  22. Tomai MA, Aelion JA, Dockter ME, Majumdar G, Spinella DG, Kotb M (1991) T cell receptor V gene usage by human T cell stimulated with the superantigen streptococcal M protein. J Exp Med 174: 285–288

    Google Scholar 

  23. Tomai MA, Schlievert PM, Kotb M (1992) Distinct T cell receptor Vβ gene usage by human T lymphocytes stimulated with the streptococcal pyrogenic exotoxins and pepM5 protein. Infect Immun 60: 701–705

    Google Scholar 

  24. Carlsson R, Dohlstein M, Baketoft A, Sjöquist J, Sjöggren HO (1984) Staphylococcal protein A does not induce production of Interferon-in human mononuclear blood cells. Cell Immunol 86: 136–145

    Google Scholar 

  25. Schrezenmeier H, Fleischer B (1987) Mitogenic activity of staphylococcal protein A is due to contaminating staphylococcal enterotoxins. J Immunol Methods 105: 133–137

    Google Scholar 

  26. Iandolo J (1989) Genetic analysis of extracellular toxins of Staphylococcus aureus. Annu Rev Microbiol 43: 375–402

    Google Scholar 

  27. Redpath MB, Foster TJ, Bailey CJ (1991) The role of the serine protease active site in the mode of action of epidermolytic toxin of Staphylococcus aureus. FEMS Microbiol Lett 65: 151–155

    Google Scholar 

  28. Bailey CJ, Redpath MB (1992) The esterolytic activity of epidermolytic toxins. Biochem J 284: 177–180

    Google Scholar 

  29. Kappler JW, Kotzin BL, Herron L, Gelfand E, Bigler RD, Boylston A, Carrel S, Posneit CD, Choi Y, Marrack P (1989) Vβ-specific stimulation of human T cells by staphylococcal toxins. Science 244: 811–814

    Google Scholar 

  30. Choi Y, Kotzin BL, Herron L, Callahan J, Marrack P, Kappler JW (1989) Interaction of Staphylococcus aureus toxin superantigens with human T cells. Proc Natl Acad Sci USA 86: 8941–8945

    Google Scholar 

  31. Herrmann T, Acolla RS, MacDonald HR (1989) Different staphylococcal enterotoxins bind preferentially to distinct MHC class II isotypes. Eur J Immunol 19: 2171–2174

    Google Scholar 

  32. Beharka AA, Armstrong JW, Iandolo JJ, Chapes SK (1994) Binding and activation of major histocompatibility complex class II-deficient macrophages by staphylococcal exotoxins. Infect Immun 62: 3907–3915

    Google Scholar 

  33. Fleischer B, Bailey CJ (1991) Recombinant epidermolytic (exfoliative) toxin a of Staphylococcus aureus is not a superantigen. Med Microbiol Immunol 180: 273–278

    Google Scholar 

  34. Fischetti VA (1989) Streptococcal M protein: molecular design and biological behavior. Clin Microbiol Rev 2: 285–314

    Google Scholar 

  35. Schmidt KH, Wadström T (1990) A secreted receptor related to M1 protein of Streptococcus pyogenes binds to fibrinogen, IgG and albumin. Zentralbl Bakteriol 273: 216–228

    Google Scholar 

  36. Akesson P, Schmidt KH, Cooney J, Björck L (1994) M1 and protein H: IgGFc-and albumin-binding streptococcal surface proteins encoded by adjacent genes. Biochem J 300: 877–886

    Google Scholar 

  37. Horstmann RD, Sievertsen HJ, Knobloch J, Fischetti VA (1988) Anti-phagocytic activity of streptococcal M protein: selective binding of complement control factor H. Proc Natl Acad Sci USA 85: 1657–1661

    Google Scholar 

  38. Schmidt KH, Mann K, Cooney J, Köhler W (1993) Multiple binding of type 3 streptococcal M protein to human fibrinogen, albumin and fibronectin. FEMS Immunol Microbiol 7: 135–144

    Google Scholar 

  39. Tomai M, Kotb M, Majumdjar G, Beachey EH (1990) Super antigenicity of Streptococcal M protein. J Exp Med 172: 359–362

    Google Scholar 

  40. Wang B, Schlievert PM, Gaber AO, Kotb M (1993) Localization of an immunologically functional region of the streptococcal superantigen pepsin-extracted fragment of type 5 M protein. J Immunol 151: 1419–1429

    Google Scholar 

  41. Watanabe Ohnishi R, Aelion J, Le Gros L, Tomai MA, Sokurenko EV, Newton D, Takahara J, Irino S, Rashed S, Kotb M (1994) Characterization of unique human TCR V specificities for a family of streptococcal superantigens represented by rheumatogenic serotypes of M protein. J Immunol 152: 2066–2073

    Google Scholar 

  42. Knöll H, Kühnemund O, Havlicek J (1979) Mitogenic and antigenic properties of group A streptococcal M protein preparations. Immunobiology 156: 537–548

    Google Scholar 

  43. Fleischer B, Schmidt KH, Gerlach D, Köhler W (1992) Separation of mitogenic activity from streptococcal M protein. Infect Immun 60: 1767–1770

    Google Scholar 

  44. Esaki Y, Fukui Y, Sudo T, Yamamoto K, Inamitsu T, Nishimura RD, Hirokawa K, Kimura A, Sasazuki R (1994) Role of human major histocompatibility complex DQ molecules in superantigenicity of streptococcus-derived protein. Infect Immun 62: 1228–1235

    Google Scholar 

  45. Robinson JH, Atherton MC, Goodacre JA, Pinkney M, Weightman H, Kehoe MA (1991) Mapping T cell epitopes in group A streptococcal type 5 M protein. Infect Immun 59: 4324–4331

    Google Scholar 

  46. Braun MA, Gerlach D, Hartwig UF, Ozegowski JH, Romagne F, Carrel S, Kohler W, Fleischer B (1993) Stimulation of human T cells by streptococcal “superantigen” erythrogenic toxins (scarlet fever toxins). J Immunol 150: 2457–2466

    Google Scholar 

  47. Mollick JA, Miller GG, Musser JM, Cook RG, Grossman D, Rich RR (1993) A novel superantigen isolated from pathogenic strains of Streptococcus pyogenes with amino-terminal homology to staphylococcal enterotoxins B and C. J Clin Invest 92: 710–719

    Google Scholar 

  48. Norrby-Teglund A, Norgren M, Holm SE, Andersson U, Andersson J (1994) Similar cytokine induction profiles of a novel streptococcal exotoxin, MF, and pyrogenic exotoxins A and B. Infect Immun 62: 3731–3738

    Google Scholar 

  49. Norrby-Teglund A, Newton D, Kotb M, Holm SE, Norgren M (1994) Superantigenic properties of the group A streptococcal exotoxin SpeF (MF). Infect Immun 62: 5227–5233

    Google Scholar 

  50. Abe J, Forrester J, Nakahara T, Lafferty JA, Kotzin BL, Leung DY (1991) Selective stimulation of human T cells with streptococcal erythrogenic toxins A and B. J Immunol 146: 3747–3750

    Google Scholar 

  51. Gerlach D, Knöll H, Köhler W, Ozegowski JH, Hribalova V (1994) Isolation and characterization of erythrogenic toxins. V. Identity of erythrogenic toxin type B and streptococcal proteinase precursor. Zentralbl Bakteriol 255: 221–233

    Google Scholar 

  52. Gerlach D, Reichhardt W, Fleischer B, Schmidt KH (1994) Separation of mitogenic and pyrogenic activity from so-called erythrogenic toxin type B (streptococcal proteinase). Zentralbl Bakteriol 280: 507–514

    Google Scholar 

  53. Bohach GA, Hauser AR, Schlievert PM (1988) Cloning of the gene, speB, for streptococcal pyrogenic exotoxin type B in Escherischia coli. Infect Immun 56: 1665–1671

    Google Scholar 

  54. Iwasaki M, Igarashi H, Hinuma Y, Yutsudo T (1993) Cloning, characterization and overexpression of a Streptococcus pyogenes gene encoding a new type of mitogenic factor. FEBS Lett 331: 187–192

    Google Scholar 

  55. Gerlach D, Günther E, Köhler W, Vettermann S, Fleischer B, Schmidt KH (1995) Isolation and characterization of a mitogen characteristic of group A streptococci (Streptococcuspyogenes). Zentralbl Bakteriol 282: 67–82

    Google Scholar 

  56. Sato H, Itoh T, Rikiishi H, Kumagai K (1994) Cytoplasmic membrane-associated protein (CAP) isolated from Streptococcus pyogenes: as a new bacterial superantigen. Microbiol Immunol 38: 139–147

    Google Scholar 

  57. Itoh T, Satoh H, Isono N, Rikiishi H, Kumagai K (1992) Mechanism of stimulation of T cells by Streptococcus pyogenes: isolation of a major mitogenic factor, cytoplasmic membrane-associated protein. Infect Immun 60: 3128–3135

    Google Scholar 

  58. Gerlach D, Alouf H, Moravek L, Pavlik M, Kohler W (1992) The characterization of two new low molecular weight proteins (LMPs) from Streptococcus pyogenes. Int J Med Microbiol Virol Parasitol Infect Dis 277: 1–9

    Google Scholar 

  59. McMillan RA, Bloomster TA, Saeed AM, Henderson KL, Zinn NE, Abernathy R, Watson DW, Greenberg RN (1987) Characterization of a fourth streptococcal pyrogenic exotoxin (SPED). FEMS Microbiol Lett 44: 317–322

    Google Scholar 

  60. Galelli A, Truffa Bachi P (1993) Urtica dioica agglutinin. A superantigenic lectin from stinging nettle rhizome. J Immunol 151: 1821–1831

    Google Scholar 

  61. Imberti L, Sottini A, Bettinardi A, Puoti M, Primi D (1991) Selective depletion in HIV infection of T cells that bear specific T cell receptor V sequences. Science 254: 860–862

    Google Scholar 

  62. Soudeyns H, Routy JP, Sekaly RP (1994) Comparative analysis of the T cell receptor V repertoire in various lymphoid tissues from HIV-infected patients: evidence for an HIV-associated superantigen. Leukemia 8 [Suppl 1]: S95-S97

    Google Scholar 

  63. Dadaglio G, Garcia S, Montagnier L, Gougeon ML (1994) Selective anergy of V 8+ T cells in human immunodeficiency virus-infected individuals. J Exp Med 179: 413–424

    Google Scholar 

  64. Boyer V, Smith LR, Ferre F, Pezzoli P, Trauger RJ, Jensen FC, Carlo DJ (1993) T cell receptor V repertoire in HIV-infection individuals: lack of evidence for selective V deletion. Clin Exp Immunol 92: 437–441

    Google Scholar 

  65. Weber GF, Cantor H (1993) HIV glycoprotein as a superantigen. A mechanism of autoimmunity and implications for a vaccination strategy. Med Hypotheses 41: 247–250

    Google Scholar 

  66. Boldt Houle DM, Rinaldo CRJ, Ehrlich GD (1993) Random depletion of T cells that bear specific T cell receptor V sequences in AIDS patients. J Leukoc Biol 54: 486–491

    Google Scholar 

  67. Chen ZW, Kou ZC, Shen L, Reimann KA, Letvin NL (1993) Conserved T cell receptor repertoire in simian immunodeficiency virus-infected rhesus monkeys. J Immunol 151: 2177–2187

    Google Scholar 

  68. Posnett DN, Kabak S, Hodtsev AS, Goldberg EA, Asch A (1993) T-cell antigen receptor V subsets are not preferentially deleted in AIDS. AIDS 7: 625–631

    Google Scholar 

  69. Piuvezam MR, Russo DM, Burns JMJ, Skeiky YA, Grabstein KH, Reed SG (1993) Characterization of responses of normal human T cells to Trypanosoma cruzi antigens. J Immunol 150: 916–924

    Google Scholar 

  70. Roessner K, Fikrig E, Russell JQ, Cooper SM, Flavell RA, Budd RC (1994) Prominent T lymphocyte response to Borrelia burgdorferi from peripheral blood of unexposed donors. Eur J Immunol 24: 320–324

    Google Scholar 

  71. Boitel B, Ermontal M, Panina Bordignon P, Mariuzza RA, Lanzavecchia A, Acuto O (1992) Prefential Vβ gene usage and lack of junctional sequence conservation among human T cell receptors specific for a tetanus toxin-derived peptide: evidence for a dominant role of a germline-encoded V region in antigen/MHC recognition. J Exp Med 175: 765–778

    Google Scholar 

  72. Murphy M, Friend DS, Pike Nobile L, Epstein LB (1992) Tumor necrosis factor-and IFN-expression in human thymus. Localization and overexpression in Down syndrome (trisomy 21). J Immunol 149: 2506–2512

    Google Scholar 

  73. Hauser AR, Schlievert PM (1990) Nucleotide sequence of the streptococcal pyrogenic exotoxin type B gene and relationship between the toxin and the streptococcal proteinase precursor. J Bacteriol 172: 4536–4541

    Google Scholar 

  74. Bowness P, Moss PA, Tranter H, Bell JI, McMichael AJ (1992) Clostridium perfringens enterotoxin is a superantigen reactive with human T cell receptors V6.9 and V22. J Exp Med 176: 893–896

    Google Scholar 

  75. Legaard PK, Le Grand RD, Misfeldt ML (1991) The superantigen Pseudomonas exotoxin A requires additional functions from accessory cells for T lymphocyte proliferation. Cell Immunol 135: 372–382

    Google Scholar 

  76. Stuart PM, Woodward JG (1992) Yersinia enterocolitica produces superantigenic activity. J Immunol 148: 225–233

    Google Scholar 

  77. Uchiyama T, Mioshi-Akiyama T, Kato H, Fujimaki W, Imanishi K, Yan XJ (1993) Superantigenic properties of a novel mitogenic substance produced by Yersinia pseudotuberculosis isolated from patients manifesting acute and systemic symptoms. J Immunol 151: 4407–4413

    Google Scholar 

  78. Abe J, Takeda T, Watanabe Y, Nakao H, Kobayashi N, Leung DY, Kohsaka T (1993) Evidence for superantigen production by Yersinia pseudotuberculosis. J Immunol 151: 4183–4188

    Google Scholar 

  79. Ohmen JD, Barnes PF, Grisso CL, Bloom BR, Modlin RL (1994) Evidence for a superantigen in human tuberculosis. Immunity 1: 35–43

    Google Scholar 

  80. Denkers EY, Caspar P, Sher A (1994) Toxoplasma gondii possesses a superantigen activity that selectively expands murine T cell receptor V5-bearing CD8+ lymphocytes. J Exp Med 180: 985–994

    Google Scholar 

  81. Hugin AW, Vacchio MS, Morse HC (1991) A virus-encoded “superantigen” in a retrovirus-induced immunodeficiency syndrome of mice. Science 252: 424–427

    Google Scholar 

  82. Donahue JP, Marrack P, Kappler JW (1993) A hVβ3.1-specific superantigen is expressed by the human cell line Raji (cited in [83])

  83. Kotzin BL, Leung DY, Kappler JW, Marrack P (1993) Superantigens and their potential role in human disease. Adv Immunol 54: 99–166

    Google Scholar 

  84. Thomson BJ, Nicholas J (1991) Superantigen function (letter). Nature 351: 530

    Google Scholar 

  85. Lafon M, Lafage M, Martinez-Arends A, Ramirez R, Vuillier F, Charron D, Lotteau V, Scott-Algara D (1992) Evidence for a viral superantigen in humans. Nature 358: 507–510

    Google Scholar 

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Authors and Affiliations

  1. Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, D-20359, Hamburg, Germany

    Bernhard Fleischer & Andreas Fuhrmann

  2. Institute for Experimental Microbiology, University of Jena, Winzerlaer Strasse 10, D-07745, Jena, Germany

    Dieter Gerlach & Karl-Hermann Schmidt

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  1. Bernhard Fleischer
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  2. Dieter Gerlach
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  3. Andreas Fuhrmann
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  4. Karl-Hermann Schmidt
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Fleischer, B., Gerlach, D., Fuhrmann, A. et al. Superantigens and pseudosuperantigens of gram-positive cocci. Med Microbiol Immunol 184, 1–8 (1995). https://doi.org/10.1007/BF00216783

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