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Superantigen Responsive T Cells Are Required for Nasopharyngeal Infection by Streptococcus Pyogenes

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Superantigen Responsive T Cells Are Required for Nasopharyngeal Infection by Streptococcus Pyogenes Western University Scholarship@Western Electronic Thesis and Dissertation Repository 3-22-2017 12:00 AM Superantigen responsive T cells are required for nasopharyngeal infection by Streptococcus pyogenes Joseph J. Zeppa The University of Western Ontario Supervisor Dr. John McCormick The University of Western Ontario Graduate Program in Microbiology and Immunology A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Joseph J. Zeppa 2017 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Immunology of Infectious Disease Commons Recommended Citation Zeppa, Joseph J., "Superantigen responsive T cells are required for nasopharyngeal infection by Streptococcus pyogenes" (2017). Electronic Thesis and Dissertation Repository. 4435. https://ir.lib.uwo.ca/etd/4435 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. i Abstract Streptococcus pyogenes is a human-specific pathogen that is responsible for serious morbidity and mortality worldwide despite being susceptible to common antibiotics. Furthermore, there is currently no licensed vaccine available against this organism. Previous research from our laboratory implicated a critical role for superantigens in a transgenic mouse model of acute nasopharyngeal infection by S. pyogenes. Herein, we are able to detect superantigen production in vivo and establish that anti-superantigen antibodies generated by either passive immunization or active vaccination with a major histocompatibility complex II-binding interface superantigen toxoid reduces S. pyogenes nasopharyngeal burden. We were also able to demonstrate that this organism requires responsive Vβ-specific T cells in order to efficiently infect the upper respiratory tract. These experiments remarkably reveal that S. pyogenes manipulates T cells to promote infection and also supports targeting superantigens as vaccine candidates to prevent nasopharyngeal carrier and subsequent disease caused by this globally important pathogen. Keywords Streptococcus pyogenes; superantigens; transgenic mouse model; nasopharyngeal infection; passive immunization; vaccination; T lymphocytes ii Co-Authorship Statement This thesis includes work that has been completed by the author and previously published. These works have been reformatted to departmental guidelines and include: Bacterial superantigens promote nasopharyngeal infection by Streptococcus pyogenes in a human MHC class II-dependent manner. Kasper, K. J., Zeppa, J. J., Wakabayashi, A. T., Xu, S. X., Mazzuca, D. M., Welch, I., Baroja, M. L., Kotb, M., Cairns, E., Cleary, P. P., Haeryfar, S. M. M., and McCormick, J. K. 2014. PLoS. Pathog. 10:e1004155. Nasopharyngeal infection of mice with Streptococcus pyogenes and in vivo detection of superantigen activity. Zeppa, J. J., Wakabayashi, A. T., Kasper, K. J., Xu, S. X., Haeryfar, S. M. M., and McCormick, J. K. 2016. Method. Mol. Biol. 1396: 95-107. Nasopharyngeal infection by Streptococcus pyogenes requires superantigen-responsive Vβ-specific T cells. Zeppa, J. J., Kasper, K. J., Mohorovic, I., Mazzuca, D. M., Haeryfar, S. M. M., and McCormick, J. K. Submitted. iii Acknowledgments To John, thank you for being a great mentor and supervisor. The time spent in your lab has continued to fuel my passion for research over the years, and has given me the tools to be successful in this crazy profession. I’ll get back to work now! To the members of the McCormick lab, past and present, thank you for your friendship and all of the good times. You have been a great group of people to spend an overwhelming majority of my time with. To my thesis advisory committee members, Drs. Haeryfar and McGavin, thank you for your guidance and insightful comments on my project. It would not have been nearly as successfully without your help. Further thanks to Dr. Haeryfar for continued use of his equipment and reagents, as well as to Dr. McGavin for editing this thesis! Thank you to The Department of Microbiology and Immunology faculty and staff. You have provided myself and countless other students with many opportunities to grow and be successful young scientists. Please continue to fuel a passion for research and all things science in the coming years! And last but not least, a huge thank you to my friends and family. For understanding and supporting me through not only this chapter of my life, but through all of them. No words can describe how appreciative I am to have all of you in my life. Thank you. iv Table of Contents Abstract ................................................................................................................................ i Co-Authorship Statement.................................................................................................... ii Acknowledgments.............................................................................................................. iii Table of Contents ............................................................................................................... iv List of Tables ..................................................................................................................... ix List of Figures ..................................................................................................................... x List of Appendices ............................................................................................................ xii List of Abbreviations ....................................................................................................... xiii Introduction .................................................................................................................... 2 Streptococcus pyogenes ......................................................................................... 2 Invasive streptococcal disease ............................................................................... 2 Superficial and locally invasive infections ............................................................ 4 Asymptomatic Carriage ......................................................................................... 6 Post-infection sequelae .......................................................................................... 7 Group A Streptococcus Genome ........................................................................... 9 Streptococcal virulence factors ........................................................................... 10 1.7.1 M Protein .................................................................................................. 10 1.7.2 Capsule ...................................................................................................... 11 1.7.3 Streptococcal pyrogenic exotoxin B protease ........................................... 12 1.7.4 Streptococcus pyogenes cell envelope protease ....................................... 13 1.7.5 Streptococcal C5a peptidase ..................................................................... 13 1.7.6 Streptococcal inhibitor of complement-mediated lysis............................. 14 1.7.7 Hemolysins ............................................................................................... 14 1.7.8 Streptokinase ............................................................................................. 15 v 1.7.9 Superantigens ............................................................................................ 16 1.7.10 Other virulence factors .............................................................................. 29 Genetic regulation in S. pyogenes ....................................................................... 29 Animal models of Group A Streptococcus infection .......................................... 31 1.9.1 Murine models of infection ....................................................................... 32 1.9.2 Non-human primate models of infection .................................................. 37 Group A streptococcal vaccines .......................................................................... 38 1.10.1 M protein vaccines .................................................................................... 38 1.10.2 Streptococcal superantigen-based vaccines .............................................. 40 1.10.3 Other vaccine candidates .......................................................................... 40 Rationale and Hypothesis .................................................................................... 41 Materials and Methods ................................................................................................. 43 Ethics statements ................................................................................................. 43 Bacterial growth conditions ................................................................................. 43 2.2.1 Escherichia coli ........................................................................................ 43 2.2.2 Streptococcus pyogenes ............................................................................ 43 2.2.3 Streptococcus pneumoniae ........................................................................ 47 Growth curves ..................................................................................................... 47 Deoxyribonucleic
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