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Interaction of Group a Streptococcus and the Plasminogen Activation System in Invasive Disease

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Interaction of Group a Streptococcus and the Plasminogen Activation System in Invasive Disease University of Wollongong Research Online University of Wollongong Thesis Collection 1954-2016 University of Wollongong Thesis Collections 2016 Interaction of Group A Streptococcus and the plasminogen activation system in invasive disease Diane Thuyvi Ly University of Wollongong Follow this and additional works at: https://ro.uow.edu.au/theses University of Wollongong Copyright Warning You may print or download ONE copy of this document for the purpose of your own research or study. The University does not authorise you to copy, communicate or otherwise make available electronically to any other person any copyright material contained on this site. You are reminded of the following: This work is copyright. Apart from any use permitted under the Copyright Act 1968, no part of this work may be reproduced by any process, nor may any other exclusive right be exercised, without the permission of the author. Copyright owners are entitled to take legal action against persons who infringe their copyright. A reproduction of material that is protected by copyright may be a copyright infringement. A court may impose penalties and award damages in relation to offences and infringements relating to copyright material. Higher penalties may apply, and higher damages may be awarded, for offences and infringements involving the conversion of material into digital or electronic form. Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong. Recommended Citation Ly, Diane Thuyvi, Interaction of Group A Streptococcus and the plasminogen activation system in invasive disease, Doctor of Philosophy thesis, School of Biological Sciences, University of Wollongong, 2016. https://ro.uow.edu.au/theses/4806 Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] Interaction of Group A Streptococcus and the Plasminogen Activation System in Invasive Disease A thesis submitted in partial fulfilment of the requirements for the award of the degree Doctor of Philosophy (PhD) From the University of Wollongong By Diane Thuyvi Ly Bachelor of Biotechnology Advanced (Honours) Illawarra Health and Medical Research Institute (IHMRI) School of Biological Sciences June, 2016 Thesis Certification This thesis is submitted in accordance with the regulations of the University of Wollongong in partial fulfilment of the degree of Doctor of Philosophy. It does not include any material published by another person except where due reference and acknowledgement is made in the text. The experimental work described in this thesis is original work and has not been submitted for a degree in any other University. Diane T. Ly June, 2016 Page | ii Acknowledgments The creation of this doctorate was not done singlehandedly, but rather, it was a result of the boundless efforts of many people who have significantly contributed to the birth of this project. The sincerest gratitude to my principle supervisor, Dr. Martina Sanderson-Smith, it is without a doubt that this degree could not have been achieved without you. Since my time in Honours, I have delved deep into the realms of science, and at times, the harsh realities were overwhelming. However, it was your guidance, encouraging ‘you can do it,’ ‘everything will be okay’ attitude, and a listening ear that helped me get through each day. I truly thank you for your selfless, understanding and kind nature that you continually show to myself, and other students. My deepest gratitude to my co-supervisors, Prof. Marie Ranson and Dr. Jason McArthur, for your mentorship and unwavering support throughout this project. I cannot emphasise my appreciation of you both always being available to offer indispensable advice, and to provide a helping hand. Collectively, I could not have asked for a better ‘support cast’ of supervisors. The spirit and passion for research that each of you convey has been inspiring, and uplifting in many ways. I would like to thank my friends and colleagues at the University of Notre Dame for their support and hospitality during my stay. I would also like to thank IHMRI staff, Katie, Clare and Tanya, for the technical assistance in the lab; animal house staff, Tracey, Maria and Carlee, for your assistance with training and animal studies; IHMRI admin and biology technical officers, for your understanding and encouragement throughout my studies. To my fellow past and present lab 312 members - Martina, Jason, Daniel, Simon, James, Dave, Jude, Jody, Cortny, Amanda, Dez, Renee, Bec, Jono, Heema, Emma, Emily and Aleta (adopted member)! I simply cannot express the impact that each of you have had on me during these years. While experimental outcomes were always a gamble and mostly frustrating, coming into the lab and spending time with each of you was always a highlight. I am indebted for all the memories of laughter, tears, and the many drinks we have shared together. The friendship and camaraderie that we share in our lab was key to the completion of this project, and for keeping my sanity. To my student cohort, what an experience it has been together! We have developed some amazing friendships, and I am truly thankful to each of you for all the memories; the stresses, frustrations, downfalls, celebrations, and milestones. Through your persistence and friendship, each of you have played an integral role in overcoming the complexities endured throughout a PhD, and have made it possible to complete this project. To my friends, I thank each and every one of you for keeping me sane, for your regular check-ins, and putting up with an absentee friend throughout this process. I am deeply appreciative for the constant positivity and encouraging attitude, and for always making me see the bigger picture when I needed it most. Lastly, with boundless love and appreciation, this feat would not have been possible without my family; Bruce, Kimmy, Danny, and Mum. There are no words to describe the enormity and sincerity of my gratitude for always unfailingly being supportive. Mum, you are my backbone, and all of this would not have been possible without you. Page | iii Table of Contents Thesis Certification .................................................................................................... ii Acknowledgments ..................................................................................................... iii Table of Contents ...................................................................................................... iv Publications Included in Thesis ............................................................................... ix Additional Publications ........................................................................................... xii Conference Proceedings.......................................................................................... xiii List of Figures .......................................................................................................... xiv List of Tables ........................................................................................................... xvi Abbreviations ......................................................................................................... xvii Abstract .................................................................................................................... xix Chapter 1 Review of the Literature .......................................................................... 1 1.1 Overview ............................................................................................................ 2 1.2 Classification of streptococci ........................................................................... 3 1.2.1 Lancefield classification ....................................................................... 3 1.2.2 M-serotyping ........................................................................................ 4 1.2.3 emm-sequence typing ........................................................................... 5 1.3 Clinical spectrum of GAS disease and epidemiology .................................... 6 1.3.1 Superficial GAS infections ................................................................... 6 1.3.2 Invasive GAS disease ........................................................................... 7 1.3.3 Post-immune sequelae .......................................................................... 8 1.3.4 Molecular epidemiology and diversity of emm-types .......................... 8 1.3.5 Current treatment for GAS infections ................................................ 11 1.4 GAS immune evasion ..................................................................................... 11 1.4.1 The innate immune system ................................................................. 12 1.4.1.1 Neutrophils ......................................................................................... 12 1.4.2 The complement system ..................................................................... 13 1.4.2.1 Activation of complement ................................................................... 14 1.4.3 GAS complement evasion strategies .................................................. 15 1.4.3.1 Acquisition of host complement regulators ........................................ 16 1.4.3.2 Degradation of complement factors by GAS proteases ...................... 18 1.4.3.3 Inhibitors
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