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

Ningyan Wang, Daiva M. Mattis, Eric J. Sundberg, Patrick M. Schlievert, David M. Kranz

Research output: Contribution to journalArticlepeer-review

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 (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-affinity Vβ 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 Vβ 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 Vβ 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.

Original languageEnglish (US)
Pages (from-to)1781-1789
Number of pages9
JournalClinical and Vaccine Immunology
Volume17
Issue number11
DOIs
StatePublished - Nov 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Clinical Biochemistry
  • Microbiology (medical)

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