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I TARGETED DELETIO of FIBRI OGE -LIKE PROTEI 2 (FGL2) E HA CES

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I TARGETED DELETIO of FIBRI OGE -LIKE PROTEI 2 (FGL2) E HA CES TARGETED DELETIO OF FIBRIOGE-LIKE PROTEI 2 (FGL2) EHACES IMMUITY I A MURIE MODEL OF ACUTE VIRAL HEPATITIS CAUSED BY LYMPHOCYTIC CHORIOMEIGITIS VIRUS (LCMV) By Ramzi Khattar A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Immunology University of Toronto © Copyright by Ramzi Khattar 2011 i Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l'édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-76778-8 Our file Notre référence ISBN: 978-0-494-76778-8 NOTICE: AVIS: The author has granted a non- L'auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l'Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distrbute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriété du droit d'auteur ownership and moral rights in this et des droits moraux qui protege cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author's permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n'y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. TARGETED DELETIO OF FIBRIOGE-LIKE PROTEI 2 (FGL2) EHACES IMMUITY I A MURIE MODEL OF ACUTE VIRAL HEPATITIS CAUSED BY LYMPHOCYTIC CHORIOMEIGITIS VIRUS (LCMV) Master of Science, 2011 Ramzi Khattar Department of Immunology University of Toronto ABSTRACT Viral hepatitis infection represents a significant epidemiological and economic burden on society. Following infection, some patients mount a blunted immune response to the virus, which ultimately can result in chronic infection. FGL2, a member of the fibrinogen-related protein superfamily, has been implicated in vitro in suppressing both innate and adaptive immune responses. In a murine model of acute viral hepatitis caused by Lymphocytic Choriomeningitis Virus strain WE, we demonstrate that FGL2 expressed by reticuloendothelial cells limits viral spread. When expressed by Treg cells FGL2 binds to FCγRIIB and prevents DC maturation and suppresses virus-specific T and B cell responses. We provide compelling evidence to suggest that hepatitis viruses utilize the FGL2-FCγRIIB pathway to evade immune detection. Inhibition of this pathway restores effective cellular and humoral antiviral immune responses towards hepatitis viruses. ii ACKOWLEDGEMETS I would like to thank my supervisor Dr. Gary Levy and members of my supervisory committee, Dr. Michael Ratcliffe, Dr. Pamela Ohashi and Dr. Reginald Gorczynski for their continued guidance and support. I acknowledge the contributions of Dr. Lang and the laboratory of Dr. Pamela Ohashi for their expertise and consultation in the LCMV model; Dr. Phillips and Dr Adeyi for their assessment of liver pathology; Dr. Shalev and Dr. Selzner for their expertise in liver disease. I would also like to acknowledge Natalie Yavorska and Darrin Gao for providing their assistance with many of the experiments. My time in the laboratory of Dr. Gary Levy has been especially enriched by the current and past members of the IBDL and research laboratory, especially Cheryl Bodnar, Justin Manuel, Jianhua Zhang, Agata Bartczak, Peter Urbanellis, Wendy Shyu, Olga Luft, Charmaine Beal, Anna Cocco, David Smookler and Ashley Lau. I would especially like to thank my family (Emile Khattar, Leila Khattar, Hani Khattar, Natasha Khattar, Randa Manoukian and Andre Manoukian) friends (Tim Tsui, Henry Biggs, Gregory Rassias, Jonathan Dickens, Chia Barsen, Terry Tai, Alice Ng, and Rashedul Amin) and colleagues from the department of immunology for their support and encouragement. I would also like to thank the employees at Starbucks café (York Mills and Leslie) for their help and support over the 11 years I have been studying there. iii TABLE OF COTETS Abstract ii Acknowledgements iii Table of Contents iv-vii List of Tables vi List of Figures vi-vii List of Abbreviations vii-x Contributions to Science xi Chapter I ITRODUCTIO 1-27 I.1 Viral Hepatitis 1-4 I.1.1 Hepatitis C Viral Infection 3 I.1.2 Current Treatments for HCV infection 4 I.2 The Immune Response 4-14 I.2.1 Innate Immunity 6 I.2.2 Innate Immune Recognition 7 I.2.3 Adaptive Immunity 9 I.2.4 Cellular Immunity 9 I.2.5 Humoral Immunity 11 I.2.6 Immune Homeostasis 13 I.3 Mechanisms of Evading Immune Recognition and Silencing the Immune Response in HCV Infection 14-16 I.3.1 Treg and HCV Infection 15 I.4 Fibrinogen-like protein 2 (FGL2) 17-21 I.4.1 Membrane-bound FGL2 18 I.4.2 Secreted FGL2 20 I.5 Lymphocytic Choriomeningitis Virus (LCMV) 22-25 I.5.1 LCMV WE 23 I. 6 Hypothesis 25-27 Chapter II MATERIALS AD METHODS 28-36 II.1 Mice 28 II.2 Virus 28 II.3 Cell Culture Media 29 II.4 Synthetic Peptides 29 II.5 Blood collection 29 II.6 Measurement of Alanine Aminotransferase (ALT) 29 iv II.7 Measurement of Plasma FGL2 29 II.8 Isolation of Lymphocytes from Spleens and Lymph Nodes 31 II.9 Isolation of Intrahepatic Mononuclear Cells 31 II.10 Histology and Immunohistochemistry 32 II.11 Morphometric Analysis 32 II.12 Chromozym Th assay 32 II.13 In Vitro Infection of Fibroblasts with LCMV in the Presence of FGL2 33 II.14 Flow Cytometry 34 II.15 Assessing LCMV-Specific Humoral Responses 34 II.16 Measurment of Neutralizing Antibody 35 II.17 Intracellular Cytokine Analysis 36 II.18 Statistical analysis 36 Chapter III RESULTS 37-56 III.1 The Prothrombinase Activity of FGL2 Prevents Early Viral Dissemination in Wild-Type Mice 37 III.2 Secreted FGL2 is Induced Following LCMV Infection of Wild-Type Mice: 40 III.3 Targeted Deletion of fgl2 Results in Enhanced Intrahepatic Antiviral Activity Following LCMV Infection: 41 III.4 Dendritic Cells Isolated From fgl2 -/- Mice Have Increased Activity Following Infection with LCMV WE: 45 III.5 Targeted Deletion of fgl2 Enhances the Frequency of Virus Specific T Cells and Increases Responsiveness to Ex Vivo Peptide Restimulation Following LCMV WE: 46 III.6 Targeted Deletion of FGL2 Enhances Humoral Responses Towards LCMV: 51 III.7 Targeted Deletion of fgl2 Enhances Immunity to LCMV Upon in Secondary Reinfection: 53 III.8 Conclusions: 55 Chapter IV DISCUSSIO 57-70 IV.1 Future Directions 69 v Chapter V REFERECES 71-91 LIST OF TABLES Introduction Table I-1 The immune response is composed of both innate and adaptive components 6 Table I-2 Route of inoculation and strain of LCMV affect disease manifestation and clearance kinetics. 23 Table I-3 Comparing the clinical outcomes of infection with different strains of LCMV with chronic HCV infection 24 LIST OF FIGURES Introduction Figure I-1 Mechanisms for clearance of HCV: 12 Figure I-2 Treg inhibit the adaptive immune response to HCV: 16 Figure I-3 The contribution of FGL2 to innate and adaptive immunity 18 Figure I-4 Proposed model for how FGL2 affects the early phase of viral infection 26 Figure I-5 Proposed model for how FGL2 affects the adaptive immune response to viral pathogens 27 Results Figure III-1.1 FGL2 prothrombinase activity is induced in macrophages upon LCMV infection 38 Figure III-1.2 Fgl2 -/- mice have enhanced viral replication prior to the induction of adaptive immunity 38 Figure III-1.3 FGL2 does not mediate its protective effects by globally inhibiting viral entry or production 39 Figure III-2.1 FGL2 is induced in vivo upon LCMV WE infection and vi remains elevated long after viral clearance from the liver 41 Figure III-3.1 Targeted deletion of fgl2 results in enhanced inflammatory responses within the liver towards LCMV infection 43 Figure III-3.2 Fgl2 -/-mice and wild-type mice have similar viral clearance kinetics, despite enhanced early viral replication in fgl2 -/- mice 44 Figure III-4.1 Fgl2 -/- mice have enhanced DC activation at day 1 following infection with LCMV WE 45 Figure III-5.1 Fgl2 -/- mice have increased frequencies of intrahepatic virus- specific CD8 + T cells following infection with LCMV WE 46 Figure III-5.2 Fgl2 -/- mice have increased frequencies of CD8 + T cells responding to peptide restimulation following LCMV infection 49 Figure III-5.3 Fgl2 -/- mice have increased frequencies of CD4 + T cells responding to peptide restimulation following LCMV infection 50 Figure III-6.1 Fgl2 -/- mice have increased humoral responses towards LCMV 52 Figure III-7.1 Fgl2 -/- mice are completely protected in secondary reinfection with LCMV WE 54 Figure III-7.2 Fgl2 -/- mice have increased frequencies of CD8 + T cells responding to peptide restimulation following LCMV reinfection 55
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