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Peptide antagonists of superantigen toxins

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Abstract

Superantigens produced by Staphylococcus aureus and Streptococcus pyogenes are among the most lethal of toxins. Toxins in this large family trigger an excessive cellular immune response leading to toxic shock. Superantigens are secreted by the bacteria as diverse natural mixtures, a complexity that demands development of broad-spectrum countermeasures. We used a rational approach to design short peptides with homology to various domains in a typical superantigen (staphylococcal enterotoxin B) and screened each peptide for its ability to antagonize, in human peripheral blood mononuclear cells, superantigen-mediated induction of the genes encoding T helper 1 cytokines that mediate shock: interleukin-2, interferon-gamma and tumor necrosis factor. A dodecamer peptide proved a potent antagonist against widely different superantigens. This peptide protected mice from killing by superantigens and it was able to rescue mice undergoing toxic shock. The antagonist peptide shows homology to a β-strand-hinge-α-helix domain that is structurally conserved among superantigens, yet currently of unknown function and remote from the binding sites for the known ligands essential for T cell activation, the major histocompatibility complex class II molecule and T cell receptor. The antagonist activity of this peptide thus identifies a novel domain in superantigens that is critical for their toxic action. The antagonist peptide provides a new tool for understanding the mechanism of excessive human immune response activation by superantigens that occurs during toxic shock and for identification of a novel target ligand that may interact with this superantigen domain.

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References

  1. Scholl, P., Diez, A., Mourad, W., Parsonnet, J., Geha, R. S. and Chatila, T., Toxic shock syndrome toxin 1 binds to major histocompatibility complex class II molecules, Proc. Natl. Acad. Sci. USA, 86 (1989) 4210–4214.

    PubMed  Google Scholar 

  2. Herman, A., Kappler, J.W., Marrack, P. and Pullen, A. M., Superantigens: Mechanisms of T-cell stimulation and role in immune responses, Ann. Rev. Immunol., 9 (1991) 745–772.

    Google Scholar 

  3. Fraser, J. D., High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR, Nature, 339 (1989) 221–223.

    PubMed  Google Scholar 

  4. Choi, Y., Herman, A., DiGiusto, D., Wade, T., Marrack, P. and Kappler, J., Residues of the variable region of the T-cell-receptor beta-chain that interact with S. aureus toxin superantigens, Nature, 346 (1990) 471–473.

    PubMed  Google Scholar 

  5. Kappler, J., Kotzin, B., Herron, L., Gelfand, E. W., Bigler, R. D., Boylston, A., Carrel, S., Posneit, C. D., Choi, Y. and Marrack, P., Vβ-specific stimulation of human T cells by staphylococcal toxins, Science, 244 (1989) 811–814.

    PubMed  Google Scholar 

  6. Janeway, C. A., Yagi, J., Katz, M. E., Jones, B., Vregop, S. and Buxser, S., T Cell responses to Mls and to bacterial proteins that mimic its behavior, Immunol. Rev., 107 (1989) 61–68.

    PubMed  Google Scholar 

  7. Choi, Y. W., Kotzin, B., Herron, L., Callahan, J., Marrack, P. and Kappler, J., Interaction of Staphylococcus aureus toxin "superantigens' with human T cells, Proc. Natl. Acad. Sci. USA, 86 (1989) 8941–8945.

    PubMed  Google Scholar 

  8. Bohach, G. A., Fast, D. J., Nelson, R. D. and Schlievert, P. M., Staphylococcal and streptococcal pyrogenic toxins involved in toxic shock syndrome and related illnesses, Crit. Rev. Microbiol., 17 (1990) 251–272.

    PubMed  Google Scholar 

  9. Kotzin, B. L., Leung, D. Y., Kappler, J. and Marrack, P., Superantigens and their potential role in human disease, Adv. Immunol., 54 (1993) 99–166.

    PubMed  Google Scholar 

  10. McCormick, J. K., Yarwood, J. M. and Schlievert, P. M., Toxic shock syndrome and bacterial superantigens: An update, Annu. Rev. Microbiol., 55 (2001) 77–104.

    PubMed  Google Scholar 

  11. Dinges, M. M., Orwin P. M. and Schlievert, P. M., Exotoxins of Staphylococcus aureus, Clin. Microbiol. Rev., 13 (2000) 16–34.

    PubMed  Google Scholar 

  12. Proft, T., Moffatt, S. L., Berkahn, C. J. and Fraser, J. D., Identification and characterization of novel superantigens from Streptococcus pyogenes, J. Exp. Med., 189 (1999) 89–102.

    PubMed  Google Scholar 

  13. McCormick, J. K., Pragman, A. A., Stolpa, J. C., Leung, D. Y. and Schlievert, P. M., Functional characterization of streptococcal pyrogenic exotoxin J, a novel superantigen, Infect. Immun., 69 (2001) 1381–1388.

    PubMed  Google Scholar 

  14. Smoot, L. M., McCormick, J. K., Smoot, J. C., Hoe, N. P., Strickland, I., Cole, R. L., Barbian, K. D., Earhart, C. A., Ohlendorf, D. H., Veasy, L. G., Hill, H. R., Leung, D. Y., Schlievert, P. M. and Musser, J. M., Characterization of two novel pyrogenic toxin superantigens made by an acute rheumatic fever clone of Streptococcus pyogenes associated with multiple disease outbreaks, Infect. Immun., 70 (2002) 7095–7104.

    PubMed  Google Scholar 

  15. Betley, M. J. and Mekalanos, J. J., Nucleotide sequence of the type A staphylococcal enterotoxin gene, J. Bacteriol., 170 (1988) 34–41.

    PubMed  Google Scholar 

  16. Blomster-Hautamaa, D. A., Kreiswirth, B. N., Kornblum, J. S., Novick, R. P. and Schlievert, P. M., The nucleotide and partial amino acid sequence of toxic shock syndrome toxin-1, J. Biol. Chem., 261 (1986) 15783–15786.

    PubMed  Google Scholar 

  17. Swaminathan, S., Furey, W., Pletcher, J. and Sax, M., Crystal structure of staphylococcal enterotoxin B, a superantigen, Nature, 359 (1992) 801–805.

    PubMed  Google Scholar 

  18. Jardetzky, T. S., Brown, J. H., Gorga, J. C., Stern, L. J., Urban, R. G., Chi, Y. I., Stauffacher, C., Strominger, J. L. and Wiley, D. C., Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen, Nature, 368 (1994) 711–718.

    PubMed  Google Scholar 

  19. Fields, B. A., Malchiodi, E. L., Li, H., Ysern, X., Stauffacher, C. V., Schlievert, P. M., Karjalainen, K. and Mariuzza, R. A., Crystal structure of a T-cell receptor beta-chain complexed with a superantigen, Nature, 384 (1996) 188–192.

    PubMed  Google Scholar 

  20. Li, H., Llera, A., Tsuchiya, D., Leder, L., Ysern, X., Schlievert, P.M., Karjalainen, K. and Mariuzza, R. A., Three-dimensional structure of the complex between a T cell receptor beta chain and the superantigen staphylococcal enterotoxin B, Immunity, 9 (1998) 807–816.

    PubMed  Google Scholar 

  21. Papageorgiou, A. C., Tranter, H. S. and Acharya K. R., Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: implications for superantigen recognition by MHC class II molecules and T-cell receptors, J. Mol. Biol., 277 (1998) 61–79.

    PubMed  Google Scholar 

  22. Leder, L., Llera, A., Lavoie, P. M., Lebedeva, M. I., Li, H., Sekaly, R. P., Bohach, G. A., Gahr, P. J., Schlievert, P. M., Karjalainen, K. and Mariuzza, R. A., A mutational analysis of the binding of staphylococcal enterotoxins B and C3 to the T cell receptor β chain and major histocompatibility complex class II, J. Exp. Med., 187 (1998) 823–833.

    PubMed  Google Scholar 

  23. Arad, G., Levy, R., Hillman, D. and Kaempfer, R., Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation, Nat. Med., 6 (2000) 414–421.

    PubMed  Google Scholar 

  24. Arad, G., Hillman, D., Levy, R. and Kaempfer, R., Superantigen antagonist blocks Th1 cytokine gene induction and lethal shock, J. Leukoc. Biol., 69 (2001) 921–927.

    PubMed  Google Scholar 

  25. Gerez, L., Arad, G., Efrat, S., Ketzinel, M. and Kaempfer, R., Post-transcriptional regulation of human interleukin-2 gene expression at processing of precursor transcripts, J. Biol. Chem., 270 (1995) 19569–19575.

    PubMed  Google Scholar 

  26. Arad, G., Tal, C., Ketzinel, M., Nussinovich, R., Deutsch, E., Schlesinger, M., Gerez, L. and Kaempfer, R., Transient expression of human IL-2 and IFN-γ genes is regulated by interaction between distinct cell subsets, Cell. Immunol., 160 (1995) 240–247.

    PubMed  Google Scholar 

  27. Jarrous, N., Osman, F. and Kaempfer, R., 2-Aminopurine selectively inhibits splicing of tumor necrosis factor alpha mRNA, Mol. Cell. Biol., 16 (1996) 2814–2822.

    PubMed  Google Scholar 

  28. Gerez, L., Madar, L., Arad, G., Sharav, T., Reshef, A., Ketzinel, M., Sayar, D., Silberberg, C. and Kaempfer, R., Aberrant regulation of interleukin-2 but not of interferon-γ gene expression in Down Syndrome (Trisomy 21), Clin. Immunol. Immunopathol., 58 (1991) 251–266.

    PubMed  Google Scholar 

  29. Kaempfer, R., Gerez, L., Farbstein, H., Madar, L., Hirschman, O., Nussinovich, R. and Shapiro, A., Prediction of response to treatment in superficial bladder carcinoma through pattern of interleukin-2 gene expression, J. Clin. Oncol., 14 (1996) 1778–1786.

    PubMed  Google Scholar 

  30. Schad, E. M., Zaitseva, I., Zaitsev, V. N., Dohlsten, M., Kalland, T., Schlievert, P.M., Ohlendorf, D. H. and Svensson, L. A., Crystal structure of the superantigen staphylococcal enterotoxin type A, EMBO J., 14 (1995) 3292–3301.

    PubMed  Google Scholar 

  31. Prasad, G. S., Earhart, C. A., Murray, D. L., Novick, R. P., Schlievert, P. M. and Ohlendorf, D. H., Structure of toxic shock syndrome toxin 1, Biochemistry, 32 (1993) 13761–13766.

    PubMed  Google Scholar 

  32. Buelow, R., O'Hehir, R. E., Schreifels, R., Kummerehl, T. J., Riley, G. and Lamb, J. R., Localization of the immunologic activity in the superantigen Staphylococcal enterotoxin B using truncated recombinant fusion proteins, J. Immunol., 148 (1992) 1–6.

    PubMed  Google Scholar 

  33. Kappler, J. W., Herman, A., Clements, J. and Marrack, P., Mutations defining functional regions of the superantigen staphylococcal enterotoxin B, J. Exp. Med., 175 (1992) 387–389.

    PubMed  Google Scholar 

  34. Hoffmann, M. L., Jablonski, L. M., Crum, K. K., Hackett, S. P., Chi, Y. I., Stauffacher, C. V., Stevens, D. L. and Bohach, G. A., Predictions of T-cell receptor-and major histocompatibility complex-binding sites on staphylococcal enterotoxin C1, Infect. Immun., 62 (1994) 3396–3407.

    PubMed  Google Scholar 

  35. Arcus, V. L., Proft, T., Sigrell, J. A., Baker, H. M., Fraser, J. D. and Baker, E. N., 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 (2000) 157–168.

    PubMed  Google Scholar 

  36. Li, H., Llera, A. and Mariuzza, R. A., Structure-function studies of T-cell receptor-superantigen interactions, Immunol. Rev., 163 (1998) 177–186.

    PubMed  Google Scholar 

  37. Sundberg, E. J., Li, H., Llera, A. S., McCormick, J. K., Tormo, J., Schlievert, P. M., Karjalainen, K. and Mariuzza, R. A., Structures of two streptococcal superantigens bound to TCR beta chains reveal diversity in the architecture of T cell signaling complexes, Structure, 10 (2002) 687–699.

    PubMed  Google Scholar 

  38. Sundberg, E. J., Li, Y. and Mariuzza, R. A., So many ways of getting in the way: Diversity in the molecular architecture of superantigen-dependent T-cell signaling complexes, Curr. Opin. Immunol., 14 (2002) 36–44.

    PubMed  Google Scholar 

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  1. Department of Molecular Virology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Raymond Kaempfer

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Correspondence to Raymond Kaempfer.

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Kaempfer, R. Peptide antagonists of superantigen toxins. Mol Divers 8, 113–120 (2004). https://doi.org/10.1023/B:MODI.0000025654.04427.44

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