title: Characterization of two novel pyrogenic toxin superantigens made by an acute rheumatic fever clone of Streptococcus pyogenes associated with multiple disease outbreaks.
abstract: 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 Vbeta1, Vbeta5.1, and Vbeta23, and SpeM had specificity for Vbeta1 and Vbeta23 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.
authors.affiliation: Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Smoot
authors.forename: John K
authors.initials: JK
authors.lastname: McCormick
authors.forename: James C
authors.initials: JC
authors.lastname: Smoot
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Hoe
authors.forename: Ian
authors.initials: I
authors.lastname: Strickland
authors.forename: Robert L
authors.initials: RL
authors.lastname: Cole
authors.forename: Kent D
authors.initials: KD
authors.lastname: Barbian
authors.forename: Cathleen A
authors.initials: CA
authors.lastname: Earhart
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Ohlendorf
authors.forename: L George
authors.initials: LG
authors.lastname: Veasy
authors.forename: Harry R
authors.initials: HR
authors.lastname: Hill
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Schlievert
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004196:Disease Outbreaks; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008969:Molecular Sequence Data; D011749:Pyrogens / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012213:Rheumatic Fever / Q000453:epidemiology* / Q000276:immunology / Q000382:microbiology; D017422:Sequence Analysis, DNA; D012772:Shock, Septic / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D013290:Streptococcal Infections / Q000453:epidemiology / Q000276:immunology / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000276:immunology*; D018089:Superantigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D011749:Pyrogens; D011994:Recombinant Proteins; C469921:SpeM protein, Streptococcus pyogenes; D018089:Superantigens; C457360:speL protein, Streptococcus pyogenes