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The Role of Interferon Epsilon in Protection Against Chlamydial The role of interferon epsilon in protection against chlamydial reproductive tract infections Jemma Rose Mayall B. Biomed Sci (Hons) June 2016 Discipline of Immunology and Microbiology School of Biomedical Sciences and Pharmacy Faculty of Health The University of Newcastle Newcastle, NSW, Australia A thesis submitted in fulfilment of the requirements for the award of a Doctor of Philosophy (Immunology and Microbiology) 1 Statement of Originality This thesis contains no material which has been accepted for the award of any other degree or diploma in any university or other tertiary institution and, to the best of my knowledge and belief, contains no material previously published or written by another person, except where due reference has been made in the text. I give consent to the final version of my thesis being made available worldwide when deposited in the University’s Digital Repository**, subject to the provisions of the Copyright Act 1968. **Unless an Embargo has been approved for a determined period. Statement of Collaboration I hereby certify that work embodied in this thesis has been done in collaboration with other researchers and carried out in other institutions. I have included as part of the thesis a statement clearly outlining the extent of collaboration, with whom and under what auspices. Statement of Authorship I hereby certify that the work embodied in this thesis contains a published paper/s/scholarly work of which I am a joint author. I have included as part of the thesis a written statement, endorsed by my supervisor, attesting to my contribution to the joint publication/s/scholarly work. X Jemma Mayall PhD Candidate 2 Acknowledgements I would like to briefly acknowledge the people who have made the completion of this thesis possible by contributing their time and support. Firstly, I would like to thank my primary supervisor, mentor, and friend, Dr. Jay Horvat. Your guidance, encouragement, and support are what have pulled me through and for all the late nights, early mornings, and weekends you have sacrificed to provide me with these things, I am truly grateful. I also owe a debt of gratitude to my co-supervisor, Prof. Phil Hansbro, whose support has also gone beyond the call of duty. Thank you for giving me the opportunity to be a part of your team and allowing me to work on this project. Thanks also to all my brilliant colleagues who I have had the pleasure of working with over the past several years. I truly feel very lucky to have had the opportunity of working with you all, and for all your assistance and friendship, you are some of the best people I know. Special thanks to my lab wife, partner in crime, and good friend, Alexandra Brown, thanks for always being there for me, dude. I would also like to thank my good friends, Courtney and Elisha Buckingham, thanks for all the love, fun, and laughs. Despite my non-existent social life, you guys have stuck around, so you must be pretty special. Finally, I would like to thank my family, especially my parents, Glenn and Dianne Mayall, who have always supported me unconditionally and have given me endless love and encouragement, and also my partner, Tim Cox, whose very important contribution to the scientific community has been feeding and housing one scientist through her PhD. Thank you for always believing in me, helping me through the rough times, and for all your unwavering love and support, you make me a better person every day. To these people I dedicate my thesis. 3 Table of contents Synopsis .................................................................................................................................... 9 Publications I have contributed to during my PhD studies ..................................................... 14 List of figures .......................................................................................................................... 21 List of tables ............................................................................................................................ 26 Abbreviations .......................................................................................................................... 29 : Introduction .............................................................................................................. 34 1.1 Sexually transmitted infections (STIs) ........................................................................ 34 1.1.1 Chlamydia reproductive tract infections (RTIs) ................................................. 34 1.1.2 Hormonal influence on infection and immunity in the female reproductive tract (RT) 42 1.2 Innate immunity in the female RT: Importance of type interferons (IFNs), natural killer (NK) cells, and inflammasomes in Chlamydia infection ............................................... 47 1.2.1 Type I IFNs ......................................................................................................... 48 1.2.2 IFNε .................................................................................................................... 54 1.2.3 NK cells .............................................................................................................. 63 1.2.4 Inflammasomes ................................................................................................... 75 1.3 PhD Studies ................................................................................................................. 88 : Characterisation of Chlamydia infection and innate responses in the female RT in IFNε-/- mice ................................................................................................................................. 90 2.1 Abstract ....................................................................................................................... 90 2.2 Introduction ................................................................................................................. 93 2.3 Methods....................................................................................................................... 98 4 2.3.1 Ethics statement .................................................................................................. 98 2.3.2 Chlamydia muridarum female RTI ..................................................................... 98 2.3.3 In vivo administration of recombinant (r)IFNε ................................................... 99 2.3.4 Total RNA extraction and bioanalysis .............................................................. 100 2.3.5 Reverse transcription and real-time qPCR ........................................................ 101 2.3.6 Chlamydia load ................................................................................................. 102 2.3.7 Flow cytometry ................................................................................................. 102 2.3.8 Microarray gene expression profiling ............................................................... 104 2.3.9 Pathway analysis ............................................................................................... 105 2.3.10 Statistics ............................................................................................................ 106 2.4 Results ....................................................................................................................... 107 2.4.1 Expression of IFNε is regulated by hormones and protects the female RT from Chlamydia infection .......................................................................................................... 107 2.4.2 IFNε deficiency alters immune cell profiles in the female RT ......................... 111 2.4.3 IFNε deficiency alters gene expression profiles in the female RT .................... 114 2.4.4 Pathway analysis of dysregulated gene transcripts in IFNε-/- mice ................... 116 2.5 Discussion ................................................................................................................. 133 : Role of NK cells in IFNε-mediated protection against Chlamydia RTI ................ 144 3.1 Abstract ..................................................................................................................... 144 3.2 Introduction ............................................................................................................... 146 3.3 Methods..................................................................................................................... 150 3.3.1 Ethics statement ................................................................................................ 150 3.3.2 C. muridarum female RTI ................................................................................. 150 5 3.3.3 In vivo NK cell depletion .................................................................................. 150 3.3.4 Flow cytometry ................................................................................................. 151 3.3.5 Total RNA extraction ........................................................................................ 154 3.3.6 Reverse transcription and real-time qPCR ........................................................ 154 3.3.7 Chlamydia load ................................................................................................. 155 3.3.8 Immunoblot analysis ......................................................................................... 155 3.3.9 Statistics ...........................................................................................................
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