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Host Cell Death in Legionella Pneumophila Pathogenesis and Immunity Wenhan Zhu Purdue University

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Host Cell Death in Legionella Pneumophila Pathogenesis and Immunity Wenhan Zhu Purdue University Purdue University Purdue e-Pubs Open Access Dissertations Theses and Dissertations Fall 2014 Host cell death in Legionella pneumophila pathogenesis and immunity Wenhan Zhu Purdue University Follow this and additional works at: https://docs.lib.purdue.edu/open_access_dissertations Part of the Biology Commons, Medical Immunology Commons, Microbiology Commons, and the Molecular Biology Commons Recommended Citation Zhu, Wenhan, "Host cell death in Legionella pneumophila pathogenesis and immunity" (2014). Open Access Dissertations. 405. https://docs.lib.purdue.edu/open_access_dissertations/405 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. *UDGXDWH6FKRRO)RUP30 5HYLVHG 0814 PURDUE UNIVERSITY GRADUATE SCHOOL Thesis/Dissertation Acceptance 7KLVLVWRFHUWLI\WKDWWKHWKHVLVGLVVHUWDWLRQSUHSDUHG %\ Wenhan Zhu (QWLWOHG Host Cell Death in Legionella pneumophila Pathogenesis and Immunity Doctor of Philosophy )RUWKHGHJUHHRI ,VDSSURYHGE\WKHILQDOH[DPLQLQJFRPPLWWHH Zhao-Qing Luo Daoguo Zhou Peter J. Hollenbeck Mark C. Hall To the best of my knowledge and as understood by the student in the Thesis/Dissertation Agreement, Publication Delay, and Certification/Disclaimer (Graduate School Form 32), this thesis/dissertation adheres to the provisions of Purdue University’s “Policy on Integrity in Research” and the use of copyrighted material. Zhao-Qing Luo $SSURYHGE\0DMRU3URIHVVRU V BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB $SSURYHGE\ Richard J. Kuhn 12/01/2014 +HDGRIWKHDepartment *UDGXDWH3URJUDP 'DWH HOST CELL DEATH IN LEGIONELLA PNEUMOPHILA PATHOGENESIS AND IMMUNITY A Dissertation Submitted to the Faculty of Purdue University by Wenhan Zhu In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2014 Purdue University West Lafayette, Indiana ii ACKNOWLEDGEMENTS I would like to express my most sincere gratitude to my family, especially to my mother. My mother is the greatest mother in the world. She made countless sacrifices so I could pursue my career and have a better life. She has always been patient, loving and supportive in the past 29 years of my life. She set me admirable examples for never to give up when the times get tough, dust up and move on when the situation is less than perfect. She also taught me to be kind, understanding and considerate to everyone around me. She is my role model, without whom I will not be able to complete this thesis, let along to obtain the degree. She is the most important reason why I work hard for my future, so I can pay her back with the best I could. I would also thank my father, who constantly encourage me to do the best; my grandmother, who is always loving and nourished me ever since I was a kid. I would like to thank my wonderful advisor, Dr. Zhao-qing Luo, who had been immensely supportive to my career at Purdue University. He is a passionate person when it comes to science. He could not sleep without knowing the result of the assay he set up and he will literally jump into the sky when he or we had exciting discoveries. His passion inspired many people including me to pursue scientific career with the burning passion. He sets up a hard-working and rewarding research environment in the lab, and always encourages lab members to explore more possibilities. Dr. Luo has high standards for his lab members in reading, understanding, connecting, and writing scientific literatures, and goes out of his way to help his lab members to achieve and surpass these standards. I iii deeply appreciate his devotion of tremendous amount of time and patience out of his incredibly busy schedule into going through my thesis word by word. From grammatical errors to logical organization, Dr. Luo sat with me and patiently guide me through these problems. He set up a wonderful example for me to pursuit my career in academia. I would also dedicate my gratitude to Dr. Yunhao Tan, who is a former labmate and good friend of mine. We studied at the same college and pursued our Ph.D degree in the same university under the same advisor. He is the most passionate and energetic scientist I have ever come across. He works more than 12 hours in lab and runs at least five miles every day. The amount of work he had done in lab is simply unbelievably large. He is simply a machine that loves science with a passion. He showed me the path of being a successful scientist is paved with hard work, and this notion continues to inspire me till today. I would also thank my former labmate Dr. Yancheng Liu, Dr. Li Xu, who are both very knowledgeable and kind. They taught me a lot when I started in Dr. Luo’s lab. I also appreciate the companion of Chelsey Dankenbring, who is always funny and make everyone around her laugh. Dr. Lili Tao, who is also a brilliant physician, had brought much fun and laughter to lab. She is smart, funny, and simply fantastic at what she does. Dr. Tao is also very generous at sharing her knowledge and expertise. I can still remember her teaching me to dissect mouse to isolate femur bones. She finished the process with such incredible efficiency and precision that no tissue, blood vessels and what so ever was damaged at all throughout the whole process. Of course, also unforgettable is her laughing at me when I was performing the same procedure, which gave me “much confidence” in the days that followed. She also brought the project that became my main focus later, which I owed tons of thanks for. Dr. Jiazhang Qiu is a fantastic labmate. He is a person that is easy to approach, lots of fun, and a great mentor. He is known to have a great pair of iv hands, which produce the most beautiful experimental results on the first attempt. His immunostaining is so gorgeous that it reminds one the stars in the sky on a beautiful night. He is also a good friend who understands my frustration both in lab and life, gives me constant encouragement and extremely useful advices, and has the magical ability to turn my bad day down-side-up. For that, I would like to express my most sincere gratitude to Dr. Jiazhang Qiu. I am truly grateful that I have three wonderful committee professors. Dr. Zhou is very passionate, kind yet critical when I present my research projects, which benefits me greatly over these years. Dr. Hollenbeck is extremely knowledgeable, always provides extremely insightful advices and always offers to help me in my projects. My project on VipD will not be completed without his generous help in quantitative microscope. Dr. Hall provided me with lots of helpful comments and great help in yeast genetics. I would also like to thank Dr. Mattoo, the expert in hardcore biochemistry, and Dr. Deng, who knows everything in fish immunology, for their generosity in providing insightful advices and equipment. The members in Luo Lab, Zhou Lab, Mattoo Lab and Deng Lab are awesome, as they had gave me much help and joy over my six years in this department. I am truly grateful for know these wonderful people. v TABLE OF CONTENTS Page NOTE ................................................................................................................... ix ABSTRACT .......................................................................................................... x CHAPTER I: GENERAL INTRODUCTION ........................................................... 1 Legionella and Type IV Secretion System ........................................................ 1 Translocation Assay System and Dot/Icm Substrate Identification ................... 6 Effector Modulation of Host Processes ............................................................. 7 Host Cell Death Pathways and L. pneumophila Infection ................................ 11 Subversion of Host Cell Death Pathways by L. pneumophila ......................... 14 Immune Recognition and L. pneumophila Infection ........................................ 17 Legionella and Underappreciated Host Immune Signaling ............................. 25 CHAPTER II: COMPREHENSIVE IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF SUBSTRATES OF THE DOT/ICM TYPE IV SECRETION SYSTEM OF LEGIONELLA PNEUMOPHILA ............................... 27 Abstract ........................................................................................................... 27 Introduction ..................................................................................................... 27 Results ............................................................................................................ 29 Construction of a library expressing Legionella-protein-β-lactamase fusions ..................................................................................................................... 29 Identification of proteins transferred by the Dot/Icm system ........................ 32 Recognition of diverse translocation signals by the Dot/ Icm transporter ..... 37 vi Page Discussion ....................................................................................................... 39 CHAPTER III: STUDY OF THE OF DOT/ICM SUBSTRATES CAPABLE OF ACTIVATING CASPASE-3 ................................................................................. 43 Abstract ........................................................................................................... 43 Introduction ..................................................................................................... 44 Results ...........................................................................................................
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