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A single, engineered protein therapeutic agent neutralizes exotoxins from both Staphylococcus aureus and Streptococcus pyogenes.

ABSTRACT: Staphylococcus aureus and Streptococcus pyogenes secrete exotoxins that act as superantigens, proteins that cause hyperimmune reactions by binding the variable domain of the T-cell receptor beta chain (V?), leading to stimulation of a large fraction of the T-cell repertoire. To develop potential neutralizing agents, we engineered V? mutants with high affinity for the superantigens staphylococcal enterotoxin B (SEB), SEC3, and streptococcal pyrogenic exotoxin A (SpeA). Unexpectedly, the high-affinity V? mutants generated against SEB cross-reacted with SpeA to a greater extent than they did with SEC3, despite greater sequence similarity between SEB and SEC3. Likewise, the V? mutants generated against SpeA cross-reacted with SEB to a greater extent than with SEC3. The structural basis of the high affinity and cross-reactivity was examined by single-site mutational analyses. The cross-reactivity seems to involve only one or two toxin residues. Soluble forms of the cross-reactive V? regions neutralized both SEB and SpeA in vivo, suggesting structure-based strategies for generating high-affinity neutralizing agents that can cross-react with multiple exotoxins.

SUBMITTER: Wang N

PROVIDER: S-EPMC2976085 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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A single, engineered protein therapeutic agent neutralizes exotoxins from both Staphylococcus aureus and Streptococcus pyogenes.

Wang Ningyan N Mattis Daiva M DM Sundberg Eric J EJ Schlievert Patrick M PM Kranz David M DM

Clinical and vaccine immunology : CVI 20100922 11

Staphylococcus aureus and Streptococcus pyogenes secrete exotoxins that act as superantigens, proteins that cause hyperimmune reactions by binding the variable domain of the T-cell receptor beta chain (Vβ), leading to stimulation of a large fraction of the T-cell repertoire. To develop potential neutralizing agents, we engineered Vβ mutants with high affinity for the superantigens staphylococcal enterotoxin B (SEB), SEC3, and streptococcal pyrogenic exotoxin A (SpeA). Unexpectedly, the high-affi ...[more]

PMID: 20861327

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Dataset Information

A single, engineered protein therapeutic agent neutralizes exotoxins from both Staphylococcus aureus and Streptococcus pyogenes.

Publications

A single, engineered protein therapeutic agent neutralizes exotoxins from both Staphylococcus aureus and Streptococcus pyogenes.

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