Defense against biologic warfare with superantigen toxins.
BACKGROUND
Superantigens produced by Staphylococcus aureus and Streptococcus pyogenes are among the most lethal of toxins. Toxins in this family trigger an excessive cellular immune response leading to toxic shock.


OBJECTIVE
To design an antagonist that is effective in vivo against a broad spectrum of superantigen toxins.


METHODS
Short peptide antagonists were selected for their ability to inhibit superantigen-induced expression of human genes for cytokines that mediate shock. The ability of these peptides to protect mice against lethal toxin challenge was examined.


RESULTS
Antagonist peptide protected mice against lethal challenge with staphylococcal enterotoxin B and toxic shock syndrome toxin-1, superantigens that share only 6% overall amino acid homology. Moreover, it rescued mice undergoing toxic shock. Antagonist peptides show homology to a beta-strand/hinge/alpha-helix domain that is structurally conserved among superantigens, yet remote from known binding sites for the major histocompatibility class II molecule and T cell receptor that function in toxic T cell hyperactivation.


CONCLUSIONS
The lethal effect of superantigens can be blocked with a peptide antagonist that inhibits their action at the top of the toxicity cascade before activation of T cells occurs. Superantigenic toxin antagonists may serve not only as countermeasures to biologic warfare but may be useful in the treatment of staphylococcal and streptococcal toxic shock, as well as in some cases of septic shock.
Kaempfer
Raymond
R
Department of Molecular Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel. kaempfer@huji.ac.il
Arad
Gila
G
Levy
Revital
R
Hillman
Dalia
D
D000818:Animals; D001427:Bacterial Toxins; D001694:Biological Warfare; D004768:Enterotoxins / Q000633:toxicity; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000209:etiology*; D013211:Staphylococcus aureus / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D018089:Superantigens / Q000633:toxicity*
D001427:Bacterial Toxins; D004768:Enterotoxins; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal