Broad-Spectrum Peptide Antagonists of Superantigen Toxins

Revital Levy; Iris Nasie; Dalia Hillman; Gila Arad; Raymond Kaempfer

doi:10.1128/9781555815844.ch14

Chapter 14 : Broad-Spectrum Peptide Antagonists of Superantigen Toxins

Authors: Revital Levy¹, Iris Nasie², Dalia Hillman³, Gila Arad⁴, Raymond Kaempfer⁵

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Affiliations: 1: Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel; 2: Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel; 3: Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel; 4: Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel; 5: Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel

Content Type: Monograph

Publication Year: 2007

Category: Bacterial Pathogenesis; Immunology

Book DOI: 10.1128/9781555815844

Chapter DOI: 10.1128/9781555815844.ch14

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Abstract:

Bacterial superantigens are among the most lethal of toxins. These stable proteins bind directly to most major histocompatibility (MHC) class II molecules and stimulate virtually all T cells bearing particular domains in the variable portion of the β-chain of the αβ T cell receptor (TCR), without need for processing by antigen-presenting cells. The peptides are capable of protecting mice from the lethal effects of superantigen toxins as widely different as staphylococcal enterotoxins (SE) SEB and toxic shock syndrome toxin 1 (TSST-1), and they can rescue animals already deeply into toxic shock. The superantigen antagonist peptides described in this chapter protect or rescue mice from lethal shock in a molar excess of as low as 20 fold over the toxin, implying that they bind tightly to a cellular target that is critical for superantigen action. The antagonist peptides described in the chapter provide a new molecular tool for understanding the mechanism of excessive human immune response activation by superantigens that occurs during toxic shock and for the identification of a novel target ligand that may interact with this superantigen domain. Removal of two amino acids from the dodecamer motif led to a significant decline in antagonist activity; this truncation may affect conformational stability or appropriate folding onto this putative receptor and reduce its affinity for the target.

Citation: Levy R, Nasie I, Hillman D, Arad G, Kaempfer R. 2007. Broad-Spectrum Peptide Antagonists of Superantigen Toxins, p 217-227. In Kotb M, Fraser J (ed), Superantigens. ASM Press, Washington, DC. doi: 10.1128/9781555815844.ch14

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Broad-Spectrum Peptide Antagonists of Superantigen Toxins

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Figure 1.

Peptide p12(150-161) is an antagonist of SEB. Inhibition of SEB-mediated induction of IL-2, IFN-γ, and TNF-β mRNA by p12(150-161) and pSEB(150-161) is shown. Aliquots of 3 X 107 PBMCs were incubated with SEB, in the absence (No peptide) or presence of the indicated peptide (10X: 10 μg/ml). At times shown, total RNA was extracted and subjected to RNase protection analysis, using a 32P-labeled IL-2, IFN-γ, TNF-β, or ribosomal RNA (rRNA) antisense RNA probe. Autoradiograms show levels of mRNA; rRNA served as loading control. Reprinted from Nature Medicine ( 3 ) with permission of the publisher.

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Figure 1.

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Figure 2.

Antagonist peptide protects and rescues mice from SEB-induced lethal shock and protects mice from TSST-1-induced lethal shock. Groups of 10 BALB/c mice were challenged with 10 μg of SEB (A) or 5 μg of TSST-1 (B), alone or in the presence of antagonist peptide added at times shown. Reprinted from the Journal of Leukocyte Biology ( 1 ) (A) and Nature Medicine ( 3 ) (B) with permission of the publishers.

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Figure 2.

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Figure 3.

Antagonist-mediated acquisition of resistance to different superantigens. Five BALB/c mice received 5 μg SEB together with p12A (A, left panel). Without further injection of p12A, survivors were rechallenged successively at 2-week intervals with SEB and SPEA (twice) and after a 9-week interval with TSST-1. At each challenge, 10 naive mice served as toxin controls. (B) Adoptive transfer of protection. Serum collected 2 weeks after TSST-1 challenge was injected into ten naive mice 1 h before challenge with 5 μg SEB. Groups of ten naive mice received serum from mice injected 2 weeks earlier with p12A or with 10 μg SEB without D-galactosamine sensitization. Eight naive mice served as SEB challenge controls. Survival remained constant beyond the times shown. Modified from Nature Medicine ( 3 ) with permission of the publisher.

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Figure 3.

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Figure 4.

A novel receptor is selectively utilized for activation of the Th1 cytokine response to superantigen. In this proposed model, to activate Th1 cytokine gene expression, a superantigen must engage not only MHC-II and TCR but also a novel receptor that is dispensable for activation of Th2 cytokine genes. Binding of antagonist peptide to this receptor results in a selective block of Th1 activation, to yield survival as well as protective immunity mediated by the action of Th2 cytokines. For clarity, antigen-presenting cell and MHC-II were omitted.

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Figure 4.

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