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Examination of Viral Infection and Host Response to Define Therapeutic Potential of Oncolytic Mammalian Orthoreovirus

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Examination of Viral Infection and Host Response to Define Therapeutic Potential of Oncolytic Mammalian Orthoreovirus Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2020 Examination of viral infection and host response to define therapeutic potential of oncolytic mammalian orthoreovirus Luke Daniel Bussiere Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Recommended Citation Bussiere, Luke Daniel, "Examination of viral infection and host response to define therapeutic potential of oncolytic mammalian orthoreovirus" (2020). Graduate Theses and Dissertations. 17855. https://lib.dr.iastate.edu/etd/17855 This Thesis is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Examination of viral infection and host response to define therapeutic potential of oncolytic mammalian orthoreovirus by Luke D. Bussiere A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Microbiology Program of Study Committee: Cathy L. Miller, Major Professor Mark R. Ackermann Bradley J. Blitvich Jeffery J. Essner Brett A. Sponseller The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2020 Copyright © Luke D. Bussiere, 2020. All rights reserved. ii TABLE OF CONTENTS ACKNOWLEDGMENTS ............................................................................................................. iv ABSTRACT .....................................................................................................................................v CHAPTER 1. GENERAL INTRODUCTION ................................................................................1 Dissertation organization ........................................................................................................... 3 References ................................................................................................................................. 4 CHAPTER 2. LITERATURE REVIEW .........................................................................................7 Introduction ............................................................................................................................... 7 Mammalian orthoreovirus ......................................................................................................... 8 Viral life cycle ......................................................................................................................... 11 Viral factories .......................................................................................................................... 14 Stress granules ......................................................................................................................... 17 MRV oncolytics ....................................................................................................................... 21 Tumor hypoxia ........................................................................................................................ 26 Prostate cancer ......................................................................................................................... 31 Conclusion ............................................................................................................................... 34 References ............................................................................................................................... 34 CHAPTER 3. CHARACTERIZATION OF A REPLICATING MAMMALIAN ORTHOREOVIRUS WITH TETRACYSTEINE-TAGGED µNS FOR LIVE-CELL VISUALIZATION OF VIRAL FACTORIES...............................................................................47 Abstract .................................................................................................................................... 47 Importance ............................................................................................................................... 48 Introduction ............................................................................................................................. 48 Results ..................................................................................................................................... 51 Discussion ................................................................................................................................ 70 Material and methods .............................................................................................................. 73 Acknowledgements ................................................................................................................. 79 Footnote ................................................................................................................................... 79 References ............................................................................................................................... 79 CHAPTER 4. INHIBITION OF HIF-1α IN PC3 CELLS IS ENHANCED IN UV- INACTIVATED VERSUS WILDTYPE MAMMALIAN ORTHOREOVIRUS INFECTION ...83 Abstract .................................................................................................................................... 83 Importance ............................................................................................................................... 84 Introduction ............................................................................................................................. 84 Results ..................................................................................................................................... 88 Discussion .............................................................................................................................. 101 Material and methods ............................................................................................................ 105 Acknowledgements ............................................................................................................... 108 References ............................................................................................................................. 108 iii CHAPTER 5. MAMMALIAN ORTHOREOVIRUS INDUCED STRESS GRANULES PROVIDE A PLATFORM FOR HIF-1α AND RACK1 ASSOCIATION RESULTING IN DECREASED HIF-1α ACCUMULATION UNDER HYPOXIA .............................................115 Abstract .................................................................................................................................. 115 Introduction ........................................................................................................................... 115 Results ................................................................................................................................... 119 Discussion .............................................................................................................................. 126 Materials and methods ........................................................................................................... 129 Acknowledgements ............................................................................................................... 132 References ............................................................................................................................. 132 CHAPTER 6. GENERAL CONCLUSION .................................................................................136 iv ACKNOWLEDGMENTS First, I would like to thank Dr. Cathy Miller for mentoring me these past five years. Dr. Miller has been a great mentor, spending much time with me talking about science, my career, and my personal life. Working with Dr. Miller has been a great experience and I am thankful for the leadership, friendship, and lab environment that she has created. I would also like to thank my committee members, Dr. Mark Ackermann, Dr. Bradley Blitvich, Dr. Jeffery Essner, and Dr. Brett Sponseller for their assistance and time on the committee. In addition, I would like to thank Dr. Brian Merkel from the University of Wisconsin-Green Bay, who encouraged me to pursue a PhD in microbiology and has been my mentor since my time in Green Bay. I also appreciate the friends I met in the Miller lab: Debarpan, Nicole, Promisree, Tianjian, and Yijun who helped me grow into a better scientist. My family has been a great support as well, and I appreciate their encouragement and prayers. I am especially thankful for my wife Emily who has encouraged me the most. Emily has listened to many presentations, read over my papers, and chatted for long periods of time about my work. She has accompanied me to the lab over the weekends or at night and has helped me whenever needed. Lastly, but most importantly I thank God for the opportunity, ability, and strength to attain my PhD. God has continually blessed my academics, and throughout all of this has drawn me closer to him, which I am most grateful for. v ABSTRACT The International Agency
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