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Eg Phd, Mphil, Dclinpsychol This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. The Role of the NS Segment of Influenza A Virus in Setting Host Range and Pathogenicity Matthew Luke Turnbull Submitted for the degree of Doctor of Philosophy The University of Edinburgh August 2016 Acknowledgements It has been an honour and a pleasure to have worked under the supervision of Prof. Paul Digard. Without his guidance and support this work would not have been possible, and for that I am extremely grateful. I also thank Prof. Bernadette Dutia, my secondary supervisor, for her encouragement and scientific discussion. I thank members of the Digard and Dutia laboratories, as well as many others at the Roslin Institute, who have provided essential help, advice, and friendship during my PhD. In particular, I thank Drs. Helen Wise, Nikki Smith, and Saira Hussain, who have all taught me essential techniques both inside and outside the lab needed to complete this work. I am also grateful to Drs. Lita Murphy, Liliane Chung, Elly Gaunt, and Seema Jasim for useful advice and discussion along the way. It has been a pleasure to work alongside fellow students Alice, Becca, Anabel, Rute and Carina. Good luck with your PhDs – I’ll be checking you have all been attending seminars when I have gone! I also need to say how much I have appreciated the support and friendship I have been blessed with over my time in Edinburgh. Laura, Tom R, Tom E, Eddie, Murray and all my teammates on the football field, all really helped me through my PhD. And of course Mum, Martin, Alex and Dom - the family. It was the good times I shared with you all I relied on when the going got tough! Finally, I’d like to thank my late Grandfather, Terry White. He strived to provide me with the best education I could have received, and for that I am eternally thankful. ii Preface Declaration I declare that this thesis was composed by myself, that the work contained herein is my own except where explicitly stated otherwise in the text, and that this work has not been submitted for any other degree or processional qualification. Signed…….............................. Date………………………… Matthew Turnbull Published material The work described in this thesis has been published in the Journal of Virology: Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity (Turnbull ML, Wise HM, Nicol MQ, Smith N, Dunfee RL, Beard PM, Jagger BW, Ligertwood Y, Hardisty GR, Xiao H, Benton DJ, Coburn AM, Paulo JA, Gygi SP, McCauley JW, Taubenberger JK, Lycett SJ, Weekes MP, Dutia BM, Digard P). 2016. Journal of Virology. 90, 9263-84. DOI: 10.1128/JVI.01205-16. The manuscript was accepted for publication at the latter stages of thesis writing, therefore it has not been referenced or discussed in this thesis. The publication includes work from all results chapters of this thesis. The publication is Open Access and can be accessed at http://jvi.asm.org/content/90/20/9263.long. A PDF is also included on CD with this thesis. iii Table of contents List of figures and tables …………………………………………………………viii Lay Summary ............................................................................................................ xi Abstract .................................................................................................................... xiii Chapter 1 Introduction to influenza A virus ........................................................... 1 1.1 General introduction to influenza A virus ..................................................... 1 1.1.1 Influenza A virus pandemics .................................................................. 4 1.2 IAV genome .................................................................................................. 7 1.2.1 Genomic viral RNA and ribonucleoproteins .......................................... 7 1.2.2 Virus gene products and protein coding strategies ............................... 10 1.3 Influenza virions .......................................................................................... 13 1.3.1 Hemagglutinin structure and cellular processing ................................. 15 1.4 Virus life cycle ............................................................................................. 16 1.4.1 Virus entry ............................................................................................ 17 1.4.2 Nuclear import of vRNPs and transcription and replication machinery .. .............................................................................................................. 19 1.4.3 Transcription and replication of the IAV genome ............................... 21 1.4.4 Viral mRNA processing ....................................................................... 23 1.4.5 Nuclear export and trafficking of vRNPs ............................................. 24 1.4.6 Virus assembly and budding ................................................................ 25 1.5 Influenza A virus evolution ......................................................................... 28 1.5.1 Antigenic drift ...................................................................................... 28 1.5.2 Antigenic shift ...................................................................................... 29 1.6 Control of influenza A virus ........................................................................ 30 1.6.1 Vaccination ........................................................................................... 30 1.6.2 Antivirals .............................................................................................. 32 1.7 Host adaptation ............................................................................................ 34 1.7.1 Viral determinants of host switching and virulence ............................. 35 1.8 The innate immune response and influenza virus infection ........................ 39 1.8.1 The interferons ..................................................................................... 39 1.8.2 Sensing of IAV infection and IFN response ........................................ 40 1.8.3 Interferon sensitive genes ..................................................................... 45 1.8.4 Viral IFN antagonists ........................................................................... 48 1.8.5 Macrophages and IAV infection .......................................................... 50 1.9 The NS segment of IAV .............................................................................. 51 iv 1.9.1 NS segment gene products ................................................................... 51 1.10 The A- and B-alleles of the NS segment ..................................................... 63 1.11 Aims and approach ...................................................................................... 65 Chapter 2 Replicative fitness of segment 8 reassortant viruses in vitro. ............. 67 2.1 Introduction ................................................................................................. 67 2.1.1 Aims ..................................................................................................... 67 2.1.2 Hypothesis ............................................................................................ 67 2.1.3 Approach .............................................................................................. 68 2.2 Results ......................................................................................................... 77 2.2.1 Virus rescue of PR8-based segment 8 reassortants .............................. 77 2.2.2 Viral protein synthesis in infected MDCK cells .................................. 80 2.2.3 Sub-cellular localisation of NS1 proteins in human cells .................... 83 2.2.4 The influence of A- and B- allele segment 8s on PR8 polymerase activity .............................................................................................................. 88 2.2.5 Growth of PR8-based reassortant viruses in human cells .................... 92 2.2.6 In vitro fitness of additional A- and B- allele segment 8 reassortant viruses. ................................................................................................. 94 2.2.7 Virus growth kinetics of PR8-based reassortants................................. 97 2.2.8 Growth of PR8-based reassortant viruses in embryonated chicken eggs .............................................................................................................. 97 2.2.9 Competition assays .............................................................................. 99 2.2.10 Fitness of avian segment 8s in Udorn72 and Cal7 backgrounds ....... 106 2.3 Discussion ................................................................................................
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