Identification and characterization of novel superantigens from Streptococcus pyogenes

Three novel streptococcal superantigen genes (spe-g, spe-h, and spe-j) were identified from the Streptococcus pyogenes M1 genomic database at the University of Oklahoma. A fourth novel gene (smez-2) was isolated from the S. pyogenes strain 2035, based on sequence homology to the streptococcal mitoge...

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Bibliographic Details
Published in:	The Journal of experimental medicine Vol. 189; no. 1; pp. 89 - 102
Main Authors:	Proft, T, Moffatt, S L, Berkahn, C J, Fraser, J D
Format:	Journal Article
Language:	English
Published:	United States The Rockefeller University Press 04-01-1999
Subjects:	Amino Acid Sequence Antigens, Bacterial - immunology Bacterial Toxins - genetics Binding, Competitive Cell Division - drug effects Cloning, Molecular Exotoxins - genetics Genes, Bacterial - genetics Histocompatibility Antigens Class II - immunology Humans Jurkat Cells Mitogens - pharmacology Models, Molecular Molecular Sequence Data Recombinant Proteins - metabolism Sequence Alignment Sequence Analysis, DNA Streptococcus pyogenes - immunology Superantigens - immunology T-Lymphocytes - immunology Zinc - metabolism
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Summary:	Three novel streptococcal superantigen genes (spe-g, spe-h, and spe-j) were identified from the Streptococcus pyogenes M1 genomic database at the University of Oklahoma. A fourth novel gene (smez-2) was isolated from the S. pyogenes strain 2035, based on sequence homology to the streptococcal mitogenic exotoxin z (smez) gene. SMEZ-2, SPE-G, and SPE-J are most closely related to SMEZ and streptococcal pyrogenic exotoxin (SPE)-C, whereas SPE-H is most similar to the staphylococcal toxins than to any other streptococcal toxin. Recombinant (r)SMEZ, rSMEZ-2, rSPE-G, and rSPE-H were mitogenic for human peripheral blood lymphocytes with half-maximal responses between 0.02 and 50 pg/ml (rSMEZ-2 and rSPE-H, respectively). SMEZ-2 is the most potent superantigen (SAg) discovered thus far. All toxins, except rSPE-G, were active on murine T cells, but with reduced potency. Binding to a human B-lymphoblastoid line was shown to be zinc dependent with high binding affinity of 15-65 nM. Evidence from modeled protein structures and competitive binding experiments suggest that high affinity binding of each toxin is to the major histocompatibility complex class II beta chain. Competition for binding between toxins was varied and revealed overlapping but discrete binding to subsets of class II molecules in the hierarchical order (SMEZ, SPE-C) > SMEZ-2 > SPE-H > SPE-G. The most common targets for the novel SAgs were human Vbeta2.1- and Vbeta4-expressing T cells. This might reflect a specific role for this subset of Vbetas in the immune defense of gram-positive bacteria.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Address correspondence to John D. Fraser, Department of Molecular Medicine, School of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. Phone: 64-9-373-7599 ext. 6036; Fax: 64-9-373-7492; E-mail: jd.fraser@auckland.ac.nz
ISSN:	0022-1007 1540-9538
DOI:	10.1084/jem.189.1.89