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The Molecular Basis of Host Range Restriction of Avian Influenza Virus Polymerases in Mammalian Hosts

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The Molecular Basis of Host Range Restriction of Avian Influenza Virus Polymerases in Mammalian Hosts The molecular basis of host range restriction of avian influenza virus polymerases in mammalian hosts Division of Investigative Sciences Faculty of Medicine Submitted for the degree of Doctor of Philosophy Olivier Moncorgé Supervised by Professor Wendy Barclay September 2012 Declaration I confirm that all work presented here is my own and that the use of all material from other sources has been properly and fully acknowledged. Olivier Moncorgé - 1 - Acknowledgements First of all I would like to thank my supervisor Professor Wendy Barclay who allowed me to start a PhD and has always been a continued source of advice, support and insight. I really enjoyed working in her lab. Apparently I enjoyed it so much that I signed for three more years. I am extremely thankful for all the past and current members of the Flu lab who made this PhD very agreeable while at the same time providing technical help, advice, scientific knowledge and food. In particular I would like to thank Manuela who initiated a part of this work. I also thank some great guys I met during those four years, in particular Dan, of course, Anna for interesting discussions, sometimes about science, Matt, Pete, Matteo (who will be a hero forever), Chris, Sahra, Deena, Jason and his muffins, Neeltje, Jon, David, Rebecca, Holly, Kim, Ruth, Lorian, Konrad, Wendy H., Hongbo, Wouter, Loupita, Miriam... My thanks also go to the members of the Virology Department who helped me and gave me precious tips and advice. I am grateful to the Wellcome Trust and the 7th Framework Programme of the European Commission (Pathogenesis and transmission of influenza in pigs, FLUPIG) for funding. Finally, it remains to thank my parents and family and of course Caro and Lucas. Thanks Caro for your patience, your advice and support and Lucas for helping me organising my piles of publications in a more subtile way. - 2 - Abstract Influenza A virus adaptation to humans is a rare but recurrent event that can result in a pandemic. The influenza polymerase, composed of the viral proteins PB1, PB2 and PA, is responsible for transcription and replication of the viral genome. Typical avian-origin influenza polymerases are restricted in human cells and polymerase subunit PB2 is particularly involved in this restriction. Residue 627 of PB2 is a glutamic acid in almost all avian influenza viruses, and mutation to a lysine is a potent enhancer of avian polymerase function in human cells. However, the underlying molecular mechanism and the cellular factors modulating avian-origin influenza replication in mammals are not known. Using a cell based replication assay in heterokaryons formed between avian and human cells, we concluded that the restriction is not due to a dominant human inhibitory factor. We also showed that supply of avian factors to human cells stimulated the activity of an avian-origin influenza polymerase and a functional screen was set up to attempt to isolate such chicken co-factor(s). We hypothesised that PB2 E627K mutation enhances the viral polymerase activity by optimizing an interaction with a human co-factor. A biochemical approach was used to try to identify this factor. Pigs are thought to be more susceptible to avian influenza than other mammalian species and are a supposed “mixing vessel” for influenza A viruses. To compare the replicative capacity of different influenza polymerases in pig, human and avian cells, an influenza polymerase assay in pig cells was set up. This assay was also used to study the impact in pig cells of known PB2 mammalian adaptive mutations. No obvious difference in the capacity of pig and human cells to support influenza polymerase activity was found, questioning the suggested susceptibility of pigs to influenza. Viruses from the avian H9N2 G1 lineage have been responsible for some human infections. Despite having none of the known mammalian signatures, we found the H9N2 G1 polymerase was active in human and pig cells. This study identified H9N2 G1 PA protein as being particularly mammalian adapted, highlighting the role of PA in influenza mammalian adaptation. - 3 - List of acronyms and abbreviations used in this project 50-92 A/Turkey/England/50-92/91 Bav A/Duck/Bavaria/1/77 bp base pairs BSA Bovine Serum Albumin CBC Cap-Binding Complex cDNA Complementary DNA cfu colony forming unit CMV Cytomegalovirus cRNA Complementary RNA CTD Carboxy-Terminal Domain Cyp Cyclophilin DMEM Dulbecco’s Modified Eagle Medium DNA Deoxyribonucleic Acid dNTPs Deoxynucleotide Triphosphates DsRED Discosoma Red fluorescent protein EDTA Ethylenediaminetetraacetic Acid eGFP Enhanced Green Fluorescent Protein EMCV Encephalomyocarditis Virus Eng195 A/England/195/09 ENV Envelope glycoprotein EST Expressed Sequence Tag FACS Fluorescence-Activated Cell Sorting FCS Fetal Calf Serum G1 A/Quail/Hong Kong/G1/97 GAG Group Specific Sntigen HA Haemagglutinin HBV Hepatitis B Virus HCV Hepatitis C Virus HDV Hepatitis Delta Virus HIV Human Immunodeficiency Virus - 4 - HPAI Highly Pathogenic Avian Influenza IFN Interferon IRES Internal Ribosome Entry Site ISA Infectious Salmon Anaemia kb kilobase kDa kilodalton LB Lysogeny Broth LC-Ms/Ms Liquid Chromatography–Mass Spectrometry LPAI Low Pathogenic Avian Influenza LTR Long Terminal Repeat LV Lentivector M1 Matrix protein 1 M2 Matrix protein 2 MDCK Madin-Derby Canine Kidney Mg Milligram ml Millilitre MOI Multiplicity Of Infection mRNA messenger Ribonucleic Acid mRNP messenger Ribonucleoprotein Mx Myxovirus-resistance protein N/A Not Applicable NA Neuraminidase NEP Nuclear Export Protein NES Nuclear Export Signal NLS Nuclear Localisation Signal NMD Nonsense-Mediated Decay NP Nucleoprotein NS1 Non-Structural protein 1 NS2 Non-Structural protein 2 PA Polymerase Acidic protein PB1 Polymerase Basic protein 1 PB1-F2 Polymerase Basic protein 1-Frame 2 - 5 - PB2 Polymerase Basic protein 2 PBS Phosphate Buffer Saline PCR Polymerase Chain Reaction pm picomol POL polymerase RLU Relative Light Units RNA Ribonucleic Acid RNAi RNA interference RNP Ribonucleoprotein SDS Sodium Sodecyl Sulphate siRNA Small interfering RNA TAP Tandem-Affinity Purification Ty05 A/turkey/Turkey/1/2005 Vic A/Victoria/3/75 vRNA Viral RNA vRNP Viral Ribonucleoprotein VSV-G Vesicular Stomatitis Virus protein G WHO World Health Organization WT Wild Type X-gal 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside - 6 - Table of Contents Declaration .............................................................................................................................- 1 - Acknowledgements ................................................................................................................- 2 - Abstract ..................................................................................................................................- 3 - List of acronyms and abbreviations used in this project .......................................................- 4 - Table of Contents ...................................................................................................................- 7 - Chapter 1. Introduction ...................................................................................................... - 17 - 1.1 Classification ........................................................................................................ - 18 - 1.2 Genome organisation .......................................................................................... - 20 - 1.3 Viral structure ...................................................................................................... - 21 - 1.4 The hosts of influenza viruses ............................................................................. - 26 - 1.4.1 Birds ............................................................................................................. - 26 - 1.4.2 Humans ........................................................................................................ - 28 - 1.4.3 Pigs ............................................................................................................... - 33 - 1.4.4 Horses .......................................................................................................... - 36 - 1.4.5 Other species ............................................................................................... - 36 - 1.5 Influenza A viral replication and host range barriers .......................................... - 37 - 1.5.1 Entering a new host ..................................................................................... - 38 - 1.5.2 Attachment .................................................................................................. - 38 - 1.5.3 Fusion and uncoating ................................................................................... - 39 - 1.5.4 Nuclear import ............................................................................................. - 41 - 1.5.5 Replication ................................................................................................... - 42 - 1.5.6 Nuclear export of ribonucleoproteins ......................................................... - 55 - 1.5.7 Assembly and release of the new virions .................................................... - 57 - - 7 - 1.5.8 Pathogenicity of influenza and immune response ...................................... - 60 - 1.5.9 Vaccines and drugs ...................................................................................... - 61 - 1.6 Direct transmission of an avian influenza virus to humans ................................ - 62 - 1.6.1
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