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Adenovirus Species B Interactions with CD46

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Adenovirus Species B Interactions with CD46 Adenovirus Species B interactions with CD46 Dan Gustafsson Institution of Clinical Microbiology, Department of Virology Umeå 2012 Responsible publisher under swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7459-368-6 ISSN: 0346-6612 Elektronisk version tillgänglig på http://umu.diva-portal.org/ Tryck/Printed by: Print&Media Umeå, Sweden 2012 To my family! Table of Contents Table of contents ……………………………………………………...……… i Abstract ……………………………………………………………………...…. iii Abbreviations …………………………………………………………………. iv Summary in Swedish, Populärvetenskaplig sammanfattning på svenska ……………………………………………………………………… vi List of papers …………………………………………………………………………… 1 Aim of thesis ………………………………………........................................... 2 Introduction ……………………………………………………........................ 3 History…………………………………………………………………………….. 3 Taxonomy…………………………………………………………………………. 3 Epidemiology and clinical features……………………………………………….. 5 Adenoviruses Structure ……………………………………………………. 6 General structure………………………………………………………………….. 6 The capsid………………………………………………………………………… 8 Major Proteins…………………………………………………………………….. 9 Hexon………………………………………………………………………………9 The Penton Base………………………………………………………………….. 10 The Fiber………………………………………………………………………….. 11 Minor Proteins…………………………………………………………………….. 14 Capsid proteins……………………………………………………………………. 14 Protein IIIa………………………………………………………………………… 14 Protein VI…………………………………………………………………………. 14 Protein VIII……………………………………………………………………….. 15 Protein IX…………………………………………………………………………. 15 Core proteins; pV, pVII, µ, pIVa2 and TP………………………………………... 16 Adenovirus Genome ………………………………………………………… 19 Early Genes……………………………………………………………………….. 20 E1A………………………………………………………………………………... 20 E1B………………………………………………………………………………... 20 E2…………………………………………………………………………………. 20 E3…………………………………………………………………………………. 21 E4…………………………………………………………………………………. 21 Delayed Early Genes……………………………………………………………… 22 Late Genes………………………………………………………………………… 22 Adenovirus lifecycle ………………………………………………………… 23 Receptors………………………………………………………………………..... 23 Coxsackie and Adenovirus Receptor (CAR)……………………………………... 23 Integrins…………………………………………………………………………... 24 CD46……………………………………………………………………………… 26 CD80/86…………………………………………………………………………... 31 Dipalmitoyl phosphatidylcholine (DPPC)………………………………………... 31 Coagulation Factors……………………………………………………………….. 31 i Heparan sulfate proteoglycans (HSPG)…………………………………………... 32 Major Histocompatibility Complex (MHC)-1……………………………………. 32 Vascular cell adhesion molecule 1 (VCAM-1)…………………………………… 32 Lactoferrin………………………………………………………………………… 33 Sialic Acid………………………………………………………………………… 33 Desmoglein 2 (DSG-2)…………..………………………………………………... 34 Internalization ………………………….…………………………………….. 34 Endocytosis of species B adenoviruses……………………….…………………... 35 Uncoating, endosomal release and intracellular trafficking………………………. 36 Transnuclear transport…………………………………………………………….. 37 Replication, assembly and release……………………………………………...…. 39 The Complement system …………………………………………...……… 40 Results …………………………………………………………………………... 44 Discussion ……………………………………………..……………………….. 51 Summary …………………………………………………………….…………. 55 Acknowledgments ……………………………………………………..…….. 56 References ……………………………………………………………...……… 59 ii ABSTRACT Adenoviruses (Ad) are double-stranded (ds) DNA, non-enveloped viruses. There are seven species (A-G) of human Ads with 52 known serotypes to date. Human Ads cause a broad range of pathologies, ranging from upper respiratory tract infections to persistent urinary tract infections. The main determinant for Ads tropism in vitro is the protruding, antenna-like, fiber protein. The fiberknob is responsible for the main interaction with the attachment receptor of the host cell. Most Ad species use the coxsackie- adenovirus receptor (CAR) as their main attachment receptor. Most species B Ads, however use CD46. CD46 is a cell surface complement regulatory protein, which is expressed on all nucleated cells in humans. Species B Ads exhibit a low seroprevalenc in the human population, making these Ads promising vector candidates for gene therapy. We have studied human Ad species B members, serotypes 7 and 11 (Ad7 and Ad11), as well as their interaction with CD46. Our first experiments showed that all species B Ads use CD46 as their main attachment receptor, with the exception of Ad3 and Ad7. Second, we performed mutational studies of recombinant Ad11p fiberknobs. These studies showed that arginine 279 in the Ad 11 fiberknob is necessary for CD46 binding. Finally we studied the effect of Ad11 binding to CD46. The results indicate that CD46 is rapidly downregulated on the cell surface after Ad11 binding. These results may provide a further understanding of the basic biology and pathology of species B Ads and may also be useful in construction of gene therapy vectors based on species B Ads. iii ABBREVIATIONS aa Amino acid Ad Adenovirus ADAM A disintegrin and metalloproteinase AIDS Acquired immune deficiency syndrome ATF1 Activating transcription factor-1 ATP Adenosine tri-phosphate CAR Coxsackie and Adenovirus Receptor CCP Complement control protein CK-2 Casein kinase-2 CHO Chinese Hamster Ovary CRM1 Chromosome region maintenance 1 CR-2 Complement receptor-2 CRP C-Reactive Protein DBP DNA-Binding Protein DNA Deoxyribonucleic Acid DPCC Dipalmitoyl phosphatidylcholine DSG Desmoglein ECM Extracellular Matrix EDTA Ethylenediaminetetraacetic acid EGFR Epidermal growthfactor receptor GON Group of nine GPI Glycosylphosphatidylinisotol HSPG Heparan sulphate proteoglycan IC Intermediate chain ICTV International Committee on Taxonomy of Viruses IFN Interferon Ig Immunoglobulin IL-12 Interleukin-12 kDa Kilodalton LDV Leu-Asp-Val LIC Light intermediate chain MAC Membrane attack complex MAPK Mitogen activated protein kinase MASP Mannan-binding lectin-associated serine proteases MBL Mannose-binding lectin MHC Major histocompatibility complex iv MMP Matrix metalloproteinases MTOC Microtubuli organizing center MV Measles virus NES Nuclear export signal NGFR Neural growthfactor receptor NLS Nuclear localization signal NPC Nuclear pore complex ORF Open reading frame PBMC Peripheral blood cells PML Promyelocytic leukemia protein PKA Protein kinase-A PKC Protein kinase-C PRM Pattern recognition molecule RBC Red blood cells RGD Arg-Gly-Asp RNA Ribonucleic acid SBAR Species B adenovirus receptor SB2AR Species B2 adenovirus receptor SCR Short consensus repeats STP Serine, threonine, proline-rich domain TP Terminal protein VCAM Vascular cell adhesion molecule v SUMMARY IN SWEDISH - POPULÄRVETENSKAPLIG SAMMANFATTNING PÅ SVENSKA Adenovirus (Ad) är icke höljeförsedda, dubbelsträngade DNA virus. Humana adenovirus delas upp i sju grupper (A-G) som innefattar i detta nu minst 52 kända serotyper. Humana adenovirus orsakar ett brett spann av olika sjukdomstillstånd, från övre luftvägsinfektioner till kroniska urinvägsinfektioner. Den största determinanten för adenovirus tropism (vilken cell viruset binder till) in vitro (i provrörsförhållanden) är fiberknoppen. Fibern är ett antenn likt protein som står ut från viruset. Dess yttersta del, fiberknoppen binder till receptorer på cellytan. De flesta adenovirus grupper använder sig av coxsackie-adenovirus receptorn (CAR) som sin primära bindningsreceptor. Grupp B adenovirus använder sig däremot av CD46. CD46 är ett protein på cellytan som uttrycks på alla humana celler med kärna och dess funktion är att reglera komplement systemet. Ganska få människor har antikroppar mot grupp B adenovirus, vilket gör dessa lämpade för genterapi. Vi har undersökt adenovirus grupp B interaktion med CD46. Vår första studie visar att alla grupp B adenovirus, förutom Ad3 och Ad7, använder CD46 som sin bindings receptor. I vår andra studie har vi utfört mutationsanalys av Ad 11 fiberknoppen för att bestämma vilken del av denna som är nödvändig för bindningen till CD46. Vi visar med våra experiment att en aminosyra, arginin vid position 279, avgör ifall Ad11 fiberkoppen binder CD46. Vi visar slutligen också att CD46 ned-regleras på cellytan som föjd av Ad11 bindning till CD46. Ovanstående resultat kan ge ytterligare insikt i den adenovirala grundbiologin. Dessa resultat kan även bidra med viktig kunskap vid konstruktionen av adenovirus vektorer för genterapi. vi LIST OF PAPERS I. CD46 is a cellular receptor for all species B adenoviruses except types 3 and 7. Marko Marttila, David Persson, Dan J Gustafsson, M Kathryn Liszewski , John P Atkinson, Göran Wadell, Niklas Arnberg. Journal of Virology. 2005 Nov;79(22):14429-36 II. The Arg279Gln [corrected] substitution in the adenovirus type 11p (Ad11p) fiber knob abolishes EDTA-resistant binding to A549 and CHO-CD46 cells, converting the phenotype to that of Ad7p. Dan J Gustafsson, Anna Segerman, Kristina Lindman, Ya-Fang Mei, Göran Wadell. Journal of Virology . 2006 Feb;80(4):1897-905. Erratum in: Journal of Virology. 2006 May;80(10):5101. III. Adenovirus 11p downregulates CD46 early in infection. Dan J Gustafsson, Emma K Andersson, Yang-Ling Hu, Marko Marttila, Kristina Lindman, Mårten Strand, Li Wang, Ya-Fang Mei. Virology . 2010 Sep 30;405(2):474-82. Epub 2010 Jul 16. 1 AIM OF THESIS The aim of this thesis was to study the interactions of species B Ads with CD46. The goal was to determine which members of species B Ads use CD46 as a receptor, which part of the Ad11 fiberknob is responsible for binding and how this interaction affects CD46. The focus has been on the early events of infection. 2 INTRODUCTION History Ads were isolated almost simultaneously by two separate
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