Bacterial Superantigens Promote Acute Nasopharyngeal Infection by Streptococcus pyogenes in a Human MHC Class II-Dependent Manner

PLoS Pathogens

Ian Welch¹  Ewa Cairns²  S. M. Mansour Haeryfar³  Miren L. Baroja⁴  Joseph J. Zeppa⁴  P. Patrick Cleary⁴  Stacey X. Xu⁴  Delfina M. Mazzuca⁴  Adrienne T. Wakabayashi⁴  Katherine J. Kasper⁴  John K. McCormick⁵  Malak Kotb⁶ 

[1] Department of Animal Care and Veterinary Services, Western University, London, Ontario, Canada;Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America;Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada;Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada;Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, United States of America;Lawson Health Research Institute, London, Ontario, Canada

关键词: Streptococcus pyogenes;    Streptococcal infections;    Respiratory infections;    Cytokines;    Antibodies;    Cloning;    Nasal concha;    Toxins;   

DOI  :  10.1371/journal.ppat.1004155

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY