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Molecular Mechanisms of Measles Virus Entry and Exit MOLECULAR MECHANISMS OF MEASLES VIRUS ENTRY AND EXIT by VÍTOR DANIEL GONÇALVES CARNEIRO A thesis submitted to the University of Birmingham For the degree of DOCTOR OF PHILOSOPHY Institute of Immunology and Immunotherapy College of Medical and Dental Sciences University of Birmingham November 2016 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Measles is a leading cause of mortality in infants in countries with suboptimal vaccination coverage. This disease is caused by a negative-strand RNA virus, measles virus (MeV). Wild-type strains of the virus use two cellular receptors to invade cells and establish infection: the signalling lymphocyte activation molecule f1 (SLAMF1), which is present on certain immune cells, and nectin-4, which is expressed in the lung epithelium. During infection, MeV can spread through the release of virions or by inducing cell-cell fusion. The aim of this thesis is to determine the molecular mechanism underlying viral entry and exit. Herein, I observed that, upon attachment to SLAMF1+ cells, MeV particles induce extensive but transient membrane blebbing and cytoskeleton contraction. MeV entry occurred simultaneously with fluid-uptake and was sensitive to inhibitors of macropinocytosis and cytoskeleton dynamics. In contrast, the cortical actin network restricted the early stages of MeV-induced cell-cell fusion, in RhoGTPases, ezrin and moesin dependent manner. By resolving the proteome of infected cells, conserved phosphorylated residues in the viral haemagglutinin were also shown to impact on dimerization and cell-cell fusion. These results suggest the manipulation of several cellular components and pathways during entry and exit of MeV. iii “ Joly Braga Santos – Symphony No. 4 Opus 16 Lento iv ACKNOWLEDGEMENTS Most of all, I would like to thank Dr Dalan Bailey, my supervisor and mentor, whose guidance, dedication and creativity have supported and inspired me throughout the past 3 years. I feel very privileged to have been his student and I can only hope that I can recreate his ingenuity and passion for science for the rest of my career. Secondly, I would like to acknowledge my co- supervisor Professor Jane McKeating for her guidance, patience and kindness throughout my PhD and to be a role model of inventiveness and excellence in virology research that I hope I can follow. I would also like to thank the present and previous members of our group, Joe, Corwin, Naz, Clare, Phil, Callum, Salman, Sha, Edouard and Tayo, for all the experimental help and enjoyable times we had together. A special thank you to Machaela and Johnny, two very talented students that I had the pleasure to supervise, whose unbelievable hard work and dedication contributed to some of the results in this thesis. A big thank you to everyone in the McKeating’s group for their help and expertise throughout my doctorate. I would also like to thank the people in Zania Stamataki’s group, Sudha, Ben, Susan, Kostas and my partner in crime Scott for their support and friendship. To my friends in and outside of Birmingham, Isa, Jaclyn, Luca, Cami, Francis, Malwina, Chris and Raquel, for making my time in the UK unforgettable. I would like to acknowledge the University of Birmingham for funding me, as well as the Microbiology Society, Biochemical Society and PrimerDesign Ltd for additional funding. Thank you to everyone in Professor Ian Goodfellow’s lab group, at the University of Cambridge, for welcoming me and teaching me so much about proteomics. Lastly, I would like to thank all my friends and family, particularly my mother and my sister, for always believing in me. v TABLE OF CONTENTS Chapter 1: General Introduction 1.1 The Morbillivirus genus ........................................................................................................... 3 1.1.1 Hosts and disease ................................................................................................................... 4 1.2 Measles virus: the causative agent of measles ............................................................................. 5 1.2.1 Measles, the disease .............................................................................................................. 6 1.2.2 Epidemiology ........................................................................................................................ 11 1.2.3 Diagnosis .............................................................................................................................. 14 1.2.4 Vaccination ........................................................................................................................... 15 1.2.5 Treatment ............................................................................................................................. 16 1.3 Genome structure ....................................................................................................................... 16 1.4 Virion structure ........................................................................................................................... 21 1.5 Transcription ............................................................................................................................... 26 1.6 Regulation of translation ............................................................................................................. 32 1.6.1 Location of transcription and replication ............................................................................. 33 1.7 Replication ................................................................................................................................... 33 1.8 Translation ................................................................................................................................... 37 1.9 Immune Response ....................................................................................................................... 38 1.9.1 Innate Immunity ................................................................................................................... 39 1.9.2 Adaptive Immunity ............................................................................................................... 40 1.10 Cellular targets of viral infection ............................................................................................... 41 1.11 Entry and exit ............................................................................................................................ 42 1.11.1 Envelope proteins .............................................................................................................. 43 1.11.2 Cellular receptors ............................................................................................................... 52 1.11.3 Virus Entry .......................................................................................................................... 71 1.11.4 Virus exit ............................................................................................................................. 84 1.12 General Aims ............................................................................................................................. 89 Chapter 2: Materials and Methods 2.1 Cell lines ...................................................................................................................................... 92 2.2 Viruses ......................................................................................................................................... 93 2.2.1 Recombinant viruses ............................................................................................................ 93 2.2.2 Virus Purification .................................................................................................................. 93 vi 2.2.3 Spinoculation ........................................................................................................................ 94 2.2.4 Virus growth curve ............................................................................................................... 94 2.3 Molecular Cloning ....................................................................................................................... 98 2.3.1 Plasmids ................................................................................................................................ 98 2.3.2 Polymerase Chain Reaction .................................................................................................. 98 2.3.3 Site-directed mutagenesis .................................................................................................. 109 2.3.4 Transformations ................................................................................................................. 110 2.3.5 DNA extraction and purification ........................................................................................ 110 2.3.6 Gel electrophoresis of DNA ...............................................................................................
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