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Prevention of Respiratory Syncytial Virus Attachment Protein Cleavage in Vero Cells Rescues Infectivity of Progeny Virions for Primary Human Airway Cultures

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Prevention of Respiratory Syncytial Virus Attachment Protein Cleavage in Vero Cells Rescues Infectivity of Progeny Virions for Primary Human Airway Cultures Prevention of Respiratory Syncytial Virus Attachment Protein Cleavage in Vero Cells Rescues Infectivity of Progeny Virions for Primary Human Airway Cultures DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jacqueline D. Corry, B.A. Graduate Program in Integrated Biomedical Science Program The Ohio State University 2015 Dissertation Committee: Mark E. Peeples, Ph.D.—Advisor Douglas M. McCarty, Ph.D. Ian Davis, DVM, Ph.D. Stefan Niewiesk, DVM, Ph.D. Copyright by Jacqueline D. Corry 2015 Abstract Live attenuated respiratory syncytial virus (RSV) vaccine candidates are produced in Vero cells, a cell line that cleaves the attachment (G) glycoprotein. As a result, Vero- derived virus is 5-fold less infectious for primary well-differentiated human airway epithelial (HAE) cultures than virus grown in HeLa. HAE cultures are isolated directly from the human airways, so it is likely that Vero-grown vaccine virus would be similarly inefficient at initiating infection of the nasal epithelium following vaccination, requiring a larger inoculum, thereby raising the cost per dose. Using protease inhibitors with increasing specificity, we identified cathepsin L as the responsible protease and confirmed that virus grown in the presence of protease inhibitors was more infectious for HAE cultures. Our evidence suggests that the G protein interacts with cathepsin L in the late endosome or lysosome via endocytic recycling. While essential for Nipah virus F protein cleavage, endocytic recycling is detrimental to the production of infectious RSV from Vero cells. We found that cathepsin L is able to cleave the G protein in Vero-grown, but not in HeLa-grown virions suggesting a difference in G protein posttranslational modification. Using mutagenesis, we identified a cluster of amino acids that are important for G protein cleavage and they contain a likely cathepsin cleavage site. Virus grown in Vero cells and containing a G protein resistant to cleavage is 5-fold more infectious for HAE than the same virus grown in Vero. Live attenuated RSV vaccine virus containing this mutation would reduce the cost of vaccine production for infants. ii Dedication I would like to dedicate this work to my family, especially: my fiancé who has been an unending source of patience, love, and humor; my mom, whose support has been unflagging in every endeavor; my dad, who is always up for competition or a giant bear hug; and my grandfather, who challenged me and made me feel that it was okay to be smart. iii Acknowledgments I would first like to sincerely thank my advisor, Dr. Mark E. Peeples. He has supported me through every step of my Ph.D. Under his tutelage, I have become a more independent scientist, a better mentor, and a better mentee. His open door policy allowed me to share science when it was still fresh and exciting. I would like to acknowledge my mentor Dr. Jeanette Marketon, who made me think, believed in me and pushed me. It is at her urging that I finally chose to apply to graduate school. I would also like to thank my lab members, whose zany antics allowed me to be myself and who made the lab a good place to be when science wasn’t working, who were cheerleaders when things got hard, who commiserated over difficult problems, who helped me find solutions, plan experiments, and who talked endlessly with me about food, the future, and of course, kitties. I would also, more seriously, like to thank them for the guidance they have provided to make me a more effective presenter. I recognize the students I have mentored while in Dr. Peeples’s lab, who helped me to understand the science better, who challenged me with thought provoking questions, and who have joined in on some of the zany antics. I acknowledge my committee members: Dr. Niewiesk, Dr. Davis, Dr. McCarthy and Dr. Flano for their support, advice and for challenging me. iv Thank you to my classmates who helped me to get through the first couple of years of graduate school relatively unscathed, especially to those that have stayed in touch! I would like to also thank Dr. Virginia Sanders, a person who so passionately insisted that I apply to IBGP little more than 2 months before the application deadline. Finally, and most importantly, I would like to thank my family and friends, without you I would not be here doing something I love. v Vita May 1999 .......................................................Abingdon High School May 2003 .......................................................B.A. Biochemistry, Knox College June 2008 to July 2011 ..................................Research Assistant I/II August 2011 to present .................................Graduate Research Associate, Biomedical Sciences Graduate Program, The Ohio State University Publications Corry J; Johnson SM; Peeples ME. Prevention of Respiratory Syncytial Virus Attachment Protein Cleavage in Vero Cells Rescues Infectivity of Progeny Virions for Primary Human Airway Cultures. Journal of Virology in press. Webster Marketon JI, Corry J; Teng, M. The respiratory syncytial virus (RSV) nonstructural proteins mediate RSV suppression of glucocorticoid receptor transactivation. Virology. 2014 Jan 20; 449: 62-69. Webster Marketon JI, Corry J. Respiratory syncytial virus (RSV) suppression of glucocorticoid receptor phosphorylation does not account for repression of transactivation. FEBS Open Bio. 2013 Jul 25; 3:305-309. Webster Marketon JI; Corry J. 2013. Poly I:C and respiratory syncytial virus (RSV) inhibit glucocorticoid receptor (GR)-mediated transactivation in lung epithelial, but not monocytic, cell lines. Virus Research. Volume 176 no. 1-2. 303-306. Burnsides C; Corry J; Alexander J; Balint C; Cosmar D; Phillips G; Webster Marketon JI. 2012. Ex vivo stimulation of whole blood as a means to determine glucocorticoid sensitivity. Journal of Inflammation Research. Vol 5. 89-97. vi Hinzey A; Alexander J; Corry J; Adams KM; Claggett AM; Traylor ZP; Davis IC; Webster Marketon JI. 2011. Respiratory syncytial virus represses glucocorticoid receptor mediated gene activation. Endocrinology. Vol. 152, no. 2: 483-494. Fields of Study Major Field: Integrated Biomedical Science Program vii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iii Acknowledgments.............................................................................................................. iv Vita ..................................................................................................................................... vi Table of Contents ............................................................................................................. viii List of Tables .................................................................................................................... xii List of Figures .................................................................................................................. xiii Chapter 1: Introduction ....................................................................................................... 1 Chapter 2: Respiratory Syncytial Virus ............................................................................. 8 Viral Discovery ............................................................................................................... 8 RSV: The Big Picture ...................................................................................................... 9 CCA-Like Viral Illness ................................................................................................ 9 Classification & Strains ............................................................................................. 11 Respiratory Syncytial Virus Spread .......................................................................... 13 The Cost of RSV Disease .......................................................................................... 15 Prophylaxis and Treatment of RSV disease .............................................................. 19 viii Respiratory Syncytial Virus: Close up .......................................................................... 20 Cell Culture................................................................................................................ 20 RNA ........................................................................................................................... 23 Viral protein identification ........................................................................................ 25 Characterization of envelope proteins ....................................................................... 30 Attachment................................................................................................................. 34 Heparin/Heparan sulfate ............................................................................................ 34 Intercellular adhesion molecule 1 .............................................................................. 37 Annexin II .................................................................................................................. 38 DC-SIGN and LC-SIGN ........................................................................................... 38 Nucleolin ..................................................................................................................
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