title: 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 (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.
authors.affiliation: Department of Biochemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL 61801, USA.
authors.forename: Ningyan
authors.initials: N
authors.lastname: Wang
authors.forename: Daiva M
authors.initials: DM
authors.lastname: Mattis
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sundberg
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Schlievert
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
mesh_terms: D000818:Animals; D000992:Antitoxins / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D003429:Cross Reactions; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005098:Exotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011485:Protein Binding; D011817:Rabbits; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D013297:Streptococcus pyogenes / Q000472:pathogenicity*; D018089:Superantigens / Q000378:metabolism*; D016019:Survival Analysis; D037521:Virulence Factors / Q000037:antagonists & inhibitors
chemical_list: D000992:Antitoxins; D001426:Bacterial Proteins; D004768:Enterotoxins; D005098:Exotoxins; D008565:Membrane Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; C117980:SpeA protein, Streptococcus pyogenes; D018089:Superantigens; D037521:Virulence Factors; C031818:enterotoxin B, staphylococcal