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Infection and Immunity, December 2002, p. 7095-7104, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.7095-7104.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Characterization of Two Novel Pyrogenic Toxin Superantigens Made by an Acute Rheumatic Fever Clone of Streptococcus pyogenes Associated with Multiple Disease Outbreaks

Laura M. Smoot,^1, John K. McCormick,^2, James C. Smoot,^1, Nancy P. Hoe,¹ Ian Strickland,³ Robert L. Cole,¹ Kent D. Barbian,¹ Cathleen A. Earhart,⁴ Douglas H. Ohlendorf,⁴ L. George Veasy,^5,6 Harry R. Hill,^5,7 Donald Y. M. Leung,³ Patrick M. Schlievert,² and James M. Musser^1*

Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840,¹ Department of Microbiology,² Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 55455,⁴ Division of Pediatric Allergy and Immunology, The National Jewish Medical and Research Center, Denver, Colorado 80262,³ Department of Pediatrics, Primary Children's Medical Center,⁵ Division of Cardiology,⁶ Division of Clinical Immunology, Departments of Pathology, Pediatrics, and Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132⁷

Received 19 June 2002/ Returned for modification 8 August 2002/ Accepted 29 August 2002

The pathogenesis of acute rheumatic fever (ARF) is poorly understood. We identified two contiguous bacteriophage genes, designated speL and speM, encoding novel inferred superantigens in the genome sequence of an ARF strain of serotype M18 group A streptococcus (GAS). speL and speM were located at the same genomic site in 33 serotype M18 isolates, and no nucleotide sequence diversity was observed in the 33 strains analyzed. Furthermore, the genes were absent in 13 non-M18 strains tested. These data indicate a recent acquisition event by a distinct clone of serotype M18 GAS. speL and speM were transcribed in vitro and upregulated in the exponential phase of growth. Purified SpeL and SpeM were pyrogenic and mitogenic for rabbit splenocytes and human peripheral blood mononuclear cells in picogram amounts. SpeL preferentially expanded human T cells expressing T-cell receptors Vß1, Vß5.1, and Vß23, and SpeM had specificity for Vß1 and Vß23 subsets, indicating that both proteins had superantigen activity. SpeL was lethal in two animal models of streptococcal toxic shock, and SpeM was lethal in one model. Serologic studies indicated that ARF patients were exposed to serotype M18 GAS, SpeL, and SpeM. The data demonstrate that SpeL and SpeM are pyrogenic toxin superantigens and suggest that they may participate in the host-pathogen interactions in some ARF patients.

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* Corresponding author. Mailing address: Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th St., Hamilton, MT 59840. Phone: (406) 363-9315. Fax: (406) 363-9427. E-mail: jmusser{at}niaid.nih.gov.

Editor: D. L. Burns

Present address: Civil and Environmental Engineering, University of Washington, Seattle, WA 98195.

Present address: The Lawson Health Research Institute, The University of Western Ontario, Grosvenor Campus, London, Ontario N6A 4V2, Canada.

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Infection and Immunity, December 2002, p. 7095-7104, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.7095-7104.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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