title: Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC Class II-dependent manner.
abstract: Establishing the genetic determinants of niche adaptation by microbial pathogens to specific hosts is important for the management and control of infectious disease. Streptococcus pyogenes is a globally prominent human-specific bacterial pathogen that secretes superantigens (SAgs) as 'trademark' virulence factors. SAgs function to force the activation of T lymphocytes through direct binding to lateral surfaces of T cell receptors and class II major histocompatibility complex (MHC-II) molecules. S. pyogenes invariably encodes multiple SAgs, often within putative mobile genetic elements, and although SAgs are documented virulence factors for diseases such as scarlet fever and the streptococcal toxic shock syndrome (STSS), how these exotoxins contribute to the fitness and evolution of S. pyogenes is unknown. Here we show that acute infection in the nasopharynx is dependent upon both bacterial SAgs and host MHC-II molecules. S. pyogenes was rapidly cleared from the nasal cavity of wild-type C57BL/6 (B6) mice, whereas infection was enhanced up to ∼10,000-fold in B6 mice that express human MHC-II. This phenotype required the SpeA superantigen, and vaccination with an MHC -II binding mutant toxoid of SpeA dramatically inhibited infection. Our findings indicate that streptococcal SAgs are critical for the establishment of nasopharyngeal infection, thus providing an explanation as to why S. pyogenes produces these potent toxins. This work also highlights that SAg redundancy exists to avoid host anti-SAg humoral immune responses and to potentially overcome host MHC-II polymorphisms.
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Kasper
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Zeppa
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
authors.forename: Adrienne T
authors.initials: AT
authors.lastname: Wakabayashi
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
authors.forename: Stacey X
authors.initials: SX
authors.lastname: Xu
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
authors.forename: Delfina M
authors.initials: DM
authors.lastname: Mazzuca
authors.affiliation: Department of Animal Care and Veterinary Services, Western University, London, Ontario, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Welch
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Miren L
authors.initials: ML
authors.lastname: Baroja
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
authors.forename: Ewa
authors.initials: E
authors.lastname: Cairns
authors.affiliation: Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: P Patrick
authors.initials: PP
authors.lastname: Cleary
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: S M Mansour
authors.initials: SM
authors.lastname: Haeryfar
authors.affiliation: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: John K
authors.initials: JK
authors.lastname: McCormick
mesh_terms: D000208:Acute Disease; D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism*; D005098:Exotoxins / Q000276:immunology / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009305:Nasopharynx / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology* / Q000517:prevention & control; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology*; D018089:Superantigens / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D005098:Exotoxins; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C117980:SpeA protein, Streptococcus pyogenes; D018089:Superantigens