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The Human Coronavirus Nucleocapsid Protein and Its Effects on the Innate Immune Response

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The Human Coronavirus Nucleocapsid Protein and Its Effects on the Innate Immune Response The Human Coronavirus Nucleocapsid Protein and Its Effects on the Innate Immune Response The Human Coronavirus Nucleocapsid Protein and Its Effects on the Innate Immune Response By Frances W. Lai, B.Sc., M.Sc. A Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy McMaster University © Copyright by Frances W. Lai, August 2013 DOCTOR OF PHILOSOPHY (2013) McMaster University (Medical Sciences) Hamilton, Ontario TITLE: The Human Coronavirus Nucleocapsid Protein and Its Effects on the Innate Immune Response AUTHOR: Frances W. Lai, B.Sc. (McMaster University), M.Sc. (University of Guelph) SUPERVISOR: Dr. Brian D. Lichty NUMBER OF PAGES: xiii, 192 ii ABSTRACT Coronaviruses are the largest known RNA viruses and infect a wide range of hosts. Human coronaviruses traditionally have been known to be the cause of the common cold and have been vastly understudied due to low morbidity and mortality. The emergence of SARS-CoV and MERS-CoV has altered the landscape of coronavirus research and proven the deadly capabilities of human coronaviruses. With two recent zoonotic events, it is increasingly important to understand the molecular biology of human coronaviruses. The coronavirus nucleocapsid protein is an essential structural protein that complexes with the viral genome. Though nucleocapsid formation is the protein’s major role, it has also been found to have other functions and effects during infection. The following research aimed to examine how the human coronavirus nucleocapsid protein affects the innate immune response in vitro. Modulation of the type I interferon response by the nucleocapsid was first investigated and the nucleocapsids were shown to have the ability to block interferon signalling. Additionally, the nucleocapsid protein was found to cause a dysregulation of transcription factor NFKB1. We propose a novel mechanism of this NFKB1 negative regulation interference. Taken together, we have further characterized the significant role of the coronavirus nucleocapsid protein in innate immune evasion. iii ACKNOWLEDGEMENTS There are many people who have supported me throughout this long journey and deserve my utmost thanks. Although it has been a bumpy road, it was filled with fantastic scenery along the way. First and foremost, to my supervisor Dr. Brian Lichty, I thank you for all of your continual support over the past several years. I believe that my academic experience would not have been complete without mentoring from someone as intelligent, thought-provoking, and helpful as you. I will never forget all of the mind-bending analogies (or the majority of them, because there were so many) that nobody else would have ever thought of but made so much sense. To my committee members Drs. Karen Mossman and James Mahony, thank you for all of your ideas and support year after year. As anxious as I was for every meeting, I always came out of them with an enhanced energy for my research. Thank you also to Dr. Dawn Bowdish for taking the time out of your busy schedule to learn about microvesicles with me. Your mentoring during our extended course was invaluable. Karen and Dawn, you are both great inspirations for women in science everywhere. To my friends and colleagues in the CGT/MIRC, you genuinely made this lengthy journey a more enjoyable experience. I feel truly lucky to have worked alongside countless talented and intellectual people, and to have made so many good friends. Thank you to my labmates Kyle Stephenson, Steve Hanson and Jo Pol for so many laughs (usually at Kyle’s expense) and for multitudinous instances of experiment triage. Thank you to Marianne Chew, Amy Gillgrass, Nicole Barra, Amanda Lee, Tamara Krneta, Sarah Reid-Yu, Ryan Shaler, Sarah McCormick, Vera Tang, and Melissa Lawson. Thank you for many cumulative hours of fantastic conversation leading to outrageous (as well as occasionally viable) ideas, both scientific and otherwise. Thank you for your constant cheerleading, complaint listening, and above all, your continual friendship. I could not have made it out with the majority of my sanity had it not been for all of you. To my parents, Patrick and Elaine Lai, I would not be where I am today without your love and support. Each day, I hope that I have made you proud. Thank you ever so much for equipping me the tools and knowledge that (I hope) have made me a proficient adult. I am also thankful to my grandmother King Chee Lai, who although did not get to see me finish this degree, valued education greatly. Thank you also to my thesis writing companion Poppy the Great Dane. Lastly, to my husband Graham Stanclik, thank you for sticking with me throughout this adventure. Your love and patience has been above and beyond what anyone could ever ask for. I am truly the lucky one. iv TABLE OF CONTENTS CHAPTER 1 REVIEW OF LITERATURE ...................................................................... 1 1.1 - THE CORONAVIRUS ................................................................................................. 2 1.1.1 - Classification and Discoveries ....................................................................... 2 1.1.2. The Virion and Genome .................................................................................. 4 1.1.3. Structural and nonstructural proteins .............................................................. 4 1.1.4. Replication .................................................................................................... 11 1.1.5. Coronavirus Pathogenesis and Immune Response ...................................... 11 1.2. THE NUCLEOCAPSID .............................................................................................. 16 1.2.1. Function in infection ...................................................................................... 16 1.2.2. Structural domains of N ................................................................................ 17 1.3. THE INNATE IMMUNE RESPONSE TO VIRAL INFECTIONS ............................................. 20 1.3.1. The Interferon Response .............................................................................. 20 1.3.1.1. Interferon and Its Induction ................................................................................20 1.3.1.2. PRRs Pertinent in RNA Virus Detection .............................................................21 1.3.1.2.1. Toll-like Receptors ......................................................................................22 1.3.1.2.2. RIG-I-like Receptors ....................................................................................25 1.3.1.3. Downstream IFN signalling ................................................................................26 1.3.1.4. Interferon Stimulated Genes ..............................................................................26 1.3.1.5. Viral evasion of IFN ...........................................................................................28 1.3.2. NF-kB: Role in antiviral response ................................................................. 29 1.3.2.1. The NF-κB Family ..............................................................................................29 1.3.2.2. NF-κB Activation Pathways ................................................................................30 1.3.2.2.1. The Canonical Pathway ..............................................................................30 1.3.2.2.2. The Noncanonical Pathway .........................................................................33 1.3.2.3. NFKB1 ...............................................................................................................33 1.3.2.4. NF-κB Responsive Genes .................................................................................34 1.3.2.5. Viral Manipulation of NF-κB ...............................................................................36 1.4. MICRORNAS ......................................................................................................... 38 1.4.1. microRNA biogenesis and gene regulation ................................................... 38 1.4.2. Current knowledge of viral exploitation of miRNA ......................................... 41 1.5. AIMS ..................................................................................................................... 43 CHAPTER 2 MATERIALS AND METHODS ............................................................... 44 2.1. CELLS AND VIRUSES. ............................................................................................. 45 2.2. PLASMIDS. ............................................................................................................ 45 2.3. IN CELL WESTERN FOR OC43 TITERING. ................................................................. 46 2.4. ANTIBODIES. ......................................................................................................... 46 2.5. WESTERN BLOTS. .................................................................................................. 48 v 2.6. VSV G-LESS ASSAY. ............................................................................................. 49 2.7. LUCIFERASE REPORTER ASSAY. ............................................................................. 49 2.8. MIR-TARGETED LUCIFERASE REPORTER ASSAY. ...................................................... 50 2.9. IMMUNOFLUORESCENCE. .......................................................................................
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