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Microrna Regulation and Human Protein Kinase Genes

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MICRORNA REGULATION AND HUMAN PROTEIN KINASE GENES REQUIRED FOR INFLUENZA VIRUS REPLICATION by LAUREN ELIZABETH ANDERSEN (Under the Direction of Ralph A. Tripp) ABSTRACT Human protein kinases (HPKs) have profound effects on cellular responses. To better understand the role of HPKs and the signaling networks that influence influenza replication, a siRNA screen of 720 HPKs was performed. From the screen, 17 “hit” HPKs (NPR2, MAP3K1, DYRK3, EPHA6, TPK1, PDK2, EXOSC10, NEK8, PLK4, SGK3, NEK3, PANK4, ITPKB, CDC2L5, CALM2, PKN3, and HK2) were validated as important for A/WSN/33 influenza virus replication, and 6 HPKs (CDC2L5, HK2, NEK3, PANK4, PLK4 and SGK3) identified as important for A/New Caledonia/20/99 influenza virus replication. Meta-analysis of the hit HPK genes identified important for influenza virus replication showed a level of overlap, most notably with the p53/DNA damage pathway. In addition, microRNAs (miRNAs) predicted to target the validated HPK genes were determined based on miRNA seed site predictions from computational analysis and then validated using a panel of miRNA agonists and antagonists. The results identify miRNA regulation of hit HPK genes identified, specifically miR-148a by targeting CDC2L5 and miR-181b by targeting SGK3, and suggest these miRNAs also have a role in regulating influenza virus replication. Together these data advance our understanding of miRNA regulation of genes critical for virus replication and are important for development novel influenza intervention strategies. INDEX WORDS: Influenza virus, host protein kinase, antiviral signaling, RNA interference, RNAi, short interfering RNA, siRNA, genome screen, microRNA, miRNA MICRORNA REGULATION AND HUMAN PROTEIN KINASE GENES REQUIRED FOR INFLUENZA VIRUS REPLICATION By LAUREN ELIZABETH ANDERSEN BS, Presbyterian College, 2005 A Dissertation Submitted to the Graduate Faculty of the University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2011 © 2011 Lauren Elizabeth Andersen All Rights Reserved MICRORNA REGULATION AND HUMAN PROTEIN KINASE GENES REQUIRED FOR INFLUENZA VIRUS REPLICATION by LAUREN ELIZABETH ANDERSEN Major Professor: Ralph A. Tripp Committee: Robert J. Hogan S. Mark Tompkins Zhen Fu David Suarez Electronic Version Approved: Maureen Grasso Dean of the Graduate School The University of Georgia December 2011 iv DEDICATION To my sisters, Emily and Lindsey, for your unfailing love and encouragement. Thank you for making me smile is all your little ways. And to my Mom and Daddy, I love you. v ACKNOWLEDGEMENTS A thank you is extended to my advisors, Dr. Ralph A. Tripp and Dr. R Jeffrey Hogan, for their guidance, instruction and support through the years. I also extend my gratitude to the other members of my committee, Dr. S. Mark Tompkins, Dr. Zhen Fu, and Dr. David A. Suarez. Collectively this group made me into a better scientist, and for this, I am indebted. I thank those who have helped me over the years, particularly Dr. Abhijeet Bakre for his continuous mentorship, extensive knowledge and encouragement. I am also grateful to current and past members of the Animal Health Research Center, especially Frank (Tank) Michel, Stephanie Gavrielides, Jamie Barber, Jackelyn Crabtree, Cheryl Jones, and Keegan Coleman. A special thank you is extended to Alaina Mooney, for her devoted friendship and intelligent conversation. I also thank the Center of Excellence for Influenza Research and Surveillance, the Georgia Research Alliance, Dharmacon ThermoFisher, the RNAi Global Consortium and The Graduate School of The University of Georgia for providing support for my training. Finally, I thank my family for their unfailing patience and support throughout my experience as a Ph.D. student. vi TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ..................................................................................... v LIST OF TABLES ................................................................................................. ix LIST OF FIGURES ............................................................................................... x CHAPTER 1 INTRODUCTION .................................................................................. 1 2 LITERATURE REVIEW ........................................................................ 5 Overview of Influenza Virus ........................................................... 5 Influenza Virus Replication .............................................................. 7 Pathogenesis of Influenza Virus and the Host Response ............. 11 Disease Intervention ..................................................................... 17 RNA Interference (RNAi) ............................................................... 19 microRNA (miRNA) Regulation in the Host Response .................. 20 RNAi and the Genome .................................................................. 22 siRNA Genome High-Throughput Screens (HTS) ......................... 24 Host Signaling Pathways important for Influenza Virus Replication… ................................................................................. 29 miRNA Regulation of Host Cell Signaling ..................................... 34 miRNA Expression During Viral Infection ...................................... 38 Next Generation Antivirals ............................................................ 41 vii References .................................................................................... 42 3 USING A RNAI GENOME SCREEN TO IDENTIFY HUMAN PROTEIN KINASE GENES REQUIRED FOR INFLUENZA A REPLICATION IN HUMAN ALVEOLAR EPITHELIAL CELLS ......................................... 71 Introduction ................................................................................... 73 siGENOME Assay ......................................................................... 76 Cell Lines and Susceptibility to Infection ....................................... 77 siRNA Controls and Transfection Conditions ................................ 78 Infection Assay .............................................................................. 80 Validation by Proof-of-Concept ..................................................... 81 Screen Results .............................................................................. 81 Normalization, Z-score Analysis and hot Identification .................. 82 Conclusions .................................................................................. 83 References .................................................................................... 92 4 MICRORNA REGULATION OF HUMAN PROTEIN KINASE GENES REQUIRED FOR INFLUENZA VIRUS REPLICATION ...................... 98 Abstract ......................................................................................... 99 Introduction ................................................................................. 101 Materials and Methods ................................................................ 104 Results ........................................................................................ 113 Discussion ................................................................................... 120 Acknowledgements ..................................................................... 129 References .................................................................................. 140 viii 5 HOST GENE TARGETS FOR NOVEL INFLUENZA THERAPIES ELUCIDATED BY HIGH-THROUGHPUT RNA INTERFERENCE SCREENS ........................................................................................ 152 Introduction ................................................................................. 153 The RNAi Pathway ...................................................................... 155 General workflow of host-pathogen screening using RNAi technology ................................................................................... 156 siRNAs and SHRNAs .................................................................. 159 miRNAs ....................................................................................... 162 Cell Types ................................................................................... 163 Viruses ........................................................................................ 164 Meta-analysis of RNAi screens for influenza virus ...................... 166 Challenges of RNAi Screening .................................................... 171 Comparing RNAi screening to analogous technologies .............. 173 Concluding Remarks ................................................................... 176 References .................................................................................. 182 6 CONCLUSIONS ............................................................................... 197 APPENDICES A SUPPLEMENTAL DATA .................................................................. 200 ix LIST OF TABLES Page Table 4.1 Human kinase genes identified important for influenza virus replication in primary screen ............................................................................... 139 Table 4.2 Host cells pathways predicted for validated genes ........................... 140 Table 5.1 Comparison of the screen stages for shRNA and siRNA screens .... 183 Table 5.2 Comparison of genome screens for influenza virus .......................... 182 Table S1. Dharmacon siRNA Sequences ......................................................... 206 Table S2. Normalized primary screen scores,
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