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Research.Pdf (5.117Mb) CELL-TO-CELL INFECTION, CELL-CELL FUSION AND PRODUCTION OF EBOLAVIRUS: MECHANISMS OF ACTION AND CELLULAR MODULATORS _____________________________________ A Dissertation presented to the Faculty of the Graduate School at the University of Missouri-Columbia _______________________________________________________ In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy _____________________________________________________ by Chunhui Miao Dr. Shan-Lu Liu, Dissertation Supervisor JULY 2016 The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled CELL-TO-CELL INFECTION, CELL-CELL FUSION AND PRODUCTION OF EBOLAVIRUS: MECHANISMS OF ACTION AND CELLULAR MODULATORS presented by Chunhui Miao, a candidate for the degree of Doctor of Philosophy, and hereby certify that, in their opinion, it is worthy of acceptance. Dr. Shan-Lu Liu Dr. Bumsuk Hahm Dr. Marc Johnson Dr. David Pintel Dr. Guoquan Zhang DEDICATION “I am a slow walker, but I never walk backwards.” - Abraham Lincoln . “Clear Head, Clever Hand and Clean Habit, C3H3”- The Motto of the Liu Lab ACKNOWLEDGMENTS First, I thank my mentor, Dr. Shan-Lu Liu for his continuous and selfless support. I feel lucky to be his student and have had a chance to learn from him during the Ph.D. training. He is the best knowledgeable and also hardest worker I have never met. I would like to express my gratitude to him for helping me throughout the Ph.D. process. He had spent tons of time teaching me how to read, how to write and how to communicate personally and scientifically. I have learned a great deal from him, not only being a scientist but also a useful person. I sincerely thank him. Secondly, I would like to thank my committee members, Dr. David Pintel, Dr. Marc Johnson, Dr. Bumsuk Hahm and Dr. Guoquan Zhang for their many valuable suggestions and constant help. I want to thank Yi-Min Zheng and numerous fellow graduate and undergraduate students for their help and discussions in the lab. In particular, I want to express my gratitude to Yi-Min’s for her many straightforward advice, which have helped me greatly whenever I felt confused. Finally, I would like to thank my family for their always being with me and supporting me during the entire Ph.D. process. Without their encouragement, love, care, and support, I could never be where I am now. Finally, I would like to express my deep gratitude to my wife Ping Cui and my father Mengjun Miao. They have given me everything they could to support me through the whole Ph.D. training. ii TABLE OF CONTENTS ACKNOWLEDGMENTS ................................................................................................ ii LIST OF TABLES ........................................................................................................... vi LIST OF FIGURES ........................................................................................................ vii ABSTRACT ...................................................................................................................... xi I. INTRODUCTION ..........................................................................................................1 1.1 Ebolavirus (EBOV) biology and disease ...................................................................1 1.1.1 The origin of EBOV ............................................................................................1 1.1.2 The epidemic of EBOV.......................................................................................2 1.1.3 Genome and proteins of EBOV ..........................................................................3 1.1.4 The life cycle of EBOV ....................................................................................16 1.1.4.1 Entry ...........................................................................................................16 1.1.4.2 Genomic replication and transcription .......................................................18 1.1.4.3 Assembly, budding and release..................................................................19 1.1.5 Antiviral treatment of EBOV. ...........................................................................25 1.2 Cell-to-cell transmission ..........................................................................................27 1.2.1 Modes of viral transmission ..............................................................................28 1.2.2 Role of biological synapses in viral cell-to-cell transmission ..........................32 1.2.2.1 Role of neural synapses (NSs) ...................................................................33 1.2.2.2 Role of immunological synapses (ISs) ......................................................36 iii 1.2.2.3 Role of virological synapses (VSs) ............................................................40 1.2.3 Experimental approaches for study of viral cell-to-cell transmission ...............42 1.2.4 Pathogenesis of viral cell-to-cell transmission .................................................45 1.3 Interferon-stimulated genes (ISGs) ..........................................................................46 1.3.1 Domains of Viperin ...........................................................................................47 1.3.2 Regulation of Viperin expression .....................................................................55 1.3.3 Biological functions of Viperin ........................................................................60 1.3.4 Virological functions of Viperin .......................................................................61 1.3.5 Escape of Viperin by virus ................................................................................65 1.3.6 Positive selection of Viperin .............................................................................67 II. CELL-CELL CONTACT PROMOTES EBOV GP-MEDIATED INFECTION 68 2.1 Abstract ....................................................................................................................68 2.2 Introduction ..............................................................................................................68 2.3 Results ......................................................................................................................70 2.4 Discussion ................................................................................................................82 2.5 Materials and Methods .............................................................................................85 III. INDUCTION OF CELL-CELL FUSION BY EBOV GLYCOPROTEIN: LOW PH IS NOT A TRIGGER ..............................................................................................109 3.1 Abstract ..................................................................................................................109 3.2 Introduction ............................................................................................................110 3.3 Results ....................................................................................................................112 iv 3.4 Discussion ..............................................................................................................131 3.5 Materials and Methods ...........................................................................................138 IV. VIPERIN RESTRICTS EBOV PRODUCTION BY INDUCING AUTOPHAGY-MEDIATED VP40 DEGRADATION ..............................................185 4.1 Abstract ..................................................................................................................185 4.2 Introduction ............................................................................................................186 4.3 Results ....................................................................................................................188 4.4 Discussion ..............................................................................................................194 4.5 Materials and Methods ...........................................................................................198 V. OVERALL SUMMARY, DISCUSSION AND FUTURE DIRECTIONS ...........211 LIST OF PUBLICATIONS ..........................................................................................220 REFERENCES ...............................................................................................................221 VITA................................................................................................................................261 v LIST OF TABLES Table 1-1: Summary of Viperin’s antiviral effects and functional domains. ....................52 vi LIST OF FIGURES Figure 1-1: The model of EBOV structure. .........................................................................8 Figure 1-2: Schematic diagram of EBOV RNA genome...................................................10 Figure 1-3: Role of VP35 in RIG-I mediated signaling. ....................................................12 Figure 1-4: Role of shed GP during EBOV infection. .......................................................14 Figure 1-5: Schematics of the EBOV life cycle.................................................................23 Figure 1-6: Modes of transmission between cells..............................................................30 Figure 1-7: The connecting microtubules between neurons have been utilized by transmission of herpesviruses. ...........................................................................................34
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