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Lsr2: an H-NS Functional Analog and Global Regulator of Mycobacterium Tuberculosis

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Lsr2: an H-NS Functional Analog and Global Regulator of Mycobacterium Tuberculosis Lsr2: an H-NS functional analog and global regulator of Mycobacterium tuberculosis by Blair Richard George Gordon A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Molecular Genetics University of Toronto © Copyright by Blair Gordon 2013 i Lsr2: an H-NS functional analog and global regulator of Mycobacterium tuberculosis Blair Gordon Doctor of Philosophy Department of Molecular Genetics University of Toronto 2012 Abstract Mycobacterium tuberculosis (M. tb), the etiological agent of tuberculosis (TB), continues to be one of the leading global health challenges causing ~2 million deaths annually. In the majority of infected individuals, the bacteria establish a latent, asymptomatic infection capable of persisting for decades with 5-10% of infected individuals developing active disease in their lifetime. Currently it is estimated that one-third of the world’s population is latently infected, representing a large reservoir for disease reactivation and subsequent spread. Latent TB infection is a paucibacillary disease in which a small heterogeneous population of bacilli is present in the body. M. tb persisters, which are characterized by reduced or altered metabolic activity and enhanced drug tolerance, are thought to be the major contributor towards latent infection and disease relapse following chemotherapy; however, the molecular mechanisms governing persisters formation remain poorly understood. My thesis concerns the characterization of the highly conserved DNA binding protein Lsr2 of mycobacteria. Previous biochemical study of Lsr2 revealed it exhibits DNA-bridging activity analogous to H-NS, an important nucleoid associated protein found in the proteobacteria. ii Here I show using in vivo complementation assays that Lsr2 is functionally equivalent to H-NS, even though these proteins share no sequence similarity. I also present genetic evidence that Lsr2 is a global regulator of M. tb that acts primarily as a transcriptional repressor. Notably, I found that Lsr2 represses a large cohort of genes induced in M.tb during in vitro models of latency including genes implicated in persister formation. I also present evidence that lsr2 is selectively inactivated during long-term hypoxia, a condition thought to be important for persister formation during latency. Lastly, I tested the lsr2deletion mutant in a mouse model of infection and found it had reduced growth relative to the WT but was still able to persist. Taken together my work implicates Lsr2 as a central regulator of persister formation and opens up exciting future research avenues on latent TB infection. iii Acknowledgments First and foremost, I would like to thank my supervisor, Dr. Jun Liu for his guidance and support over the past five years. Through the highs and the lows Jun has been there for me. Following his example, I feel I have developed as a critical thinker and problem solver. I am also indebted to past and present Liu lab members: Vanessa Tran, Andrea Leung, Ming Li, Linru Wang, Howard Song, Alina Nakhamchik, Jackie Liu, Rachid Nessar, Anna Sintsova and Nathan Ma. I am grateful for your support, constructive criticism and sense of camaraderie we shared during our time together in the lab. I also thank my supervisory committee members, Drs Barbara Funnell, Timothy Hughes and William Navarre. Their guidance and support has been invaluable throughout my graduate career. In particular, Will has been a great mentor and support with his expertise on H-NS. I am thankful for all of our impromptu chats as well as his career and life advice. The Navarre lab members, past and present, have been a great support and I consider many of them friends. I would like to acknowledge Sabrina Ali, Betty Zou, Steven Hersch, and Robin Imperial. As well, I also acknowledge past and present members of the Gray-Owen lab, many of whom were older than I was and served as role models, for sharing their knowledge and advice with me. This includes Michael Brooks, Nancy So, Wendy Dobson-Belaire and Gord McSheffrey. Science is rarely an independent endeavour and so I would like to thank my collaborators along the way. This includes the Hughes Lab members who shared their technical knowledge and helped with analysis. Thank you to Drs Harm van Bakel, Atina Cote and Matthew Weirauch. I also thank Dr. Bin Xia and his graduate student Yifei Li from Peking University in Beijing for their fantastic structural work. Lastly, I want to thank family and friends who have and continue to enrich my life outside of the lab. My parents Suzanne Fisk and Richard Gordon fostered my interest and curiousity in the natural world while growing up and have been instrumental in getting me to where I am today. Along with my siblings Graeme, Laura and Mark, they have been a great support for me through the tough times. My late Grandmother Marjorie Fisk imparted her love of learning and higher education and remains an inspiration to me. I want to thank all of the iv friends I have made in Toronto both in and out of graduate school. Specifically I thank Rade Sajic, Erica Tong, Natasha Christie-Holmes, Mark Czuczman, Madhav Jagannathan (for organizing all the social events) and my mountain biking buddies Alejandro Llabres and Alex Bull. Thank you to my cat MacDuff who sat in my lap and kept me company while writing this volume. Finally, I want to express my heartfelt gratitude to Sue Li for her unwavering support and her thoughtful insights. I could not have made it without you! v Table of Contents ACKNOWLEDGMENTS .......................................................................................................... IV TABLE OF CONTENTS ........................................................................................................... VI LIST OF TABLES ........................................................................................................................ X LIST OF ABBREVIATIONS .................................................................................................... XI LIST OF FIGURES ................................................................................................................. XIII CHAPTER 1: GENERAL INTRODUCTION ........................................................................... 1 1.1 An introduction to mycobacteria ...................................................................................................................... 2 1.1.1 The pathogenic mycobacteria .................................................................................................................. 2 1.1.2 The environmental mycobacteria ............................................................................................................ 4 1.2 Mycobacterium tuberculosis pathogenesis and virulence factors .................................................................... 4 1.2.1 Global burden of TB on human health ................................................................................................... 4 1.2.2 Pathogenesis and immunology ................................................................................................................ 5 1.2.3 Animals models of M. tb virulence and persistence ............................................................................... 6 1.2.4 The live attenuated vaccine BCG ............................................................................................................ 9 1.2.5 The RD1 deletion and the attenuation of BCG .................................................................................... 10 1.2.6 Individual BCG strains are mutated for M. tb virulence factors ........................................................ 10 1.3 Metabolism and dormancy .............................................................................................................................. 12 1.3.1 Dormancy ................................................................................................................................................ 12 1.3.2 Evidence for dormancy and M. tb persisters during infection ............................................................ 13 1.3.3 Persisters and their molecular mechanisms of formation ................................................................... 13 1.3.4 Oxygen and latency ................................................................................................................................ 15 1.3.5 Carbon metabolism ................................................................................................................................ 17 1.4 The H-NS protein ............................................................................................................................................. 21 1.4.1 H-NS is a bacterial nucleoid-associated proteins ................................................................................. 21 1.4.2 H-NS: a pleiotropic transcriptional regulator ...................................................................................... 21 1.4.3 Biochemical and structural properties of H-NS ................................................................................... 23 vi 1.5 Lsr2 of Mycobacteria ....................................................................................................................................... 26 1.6 Thesis Rationale and Outline .......................................................................................................................... 26 CHAPTER 2: LSR2 OF MYCOBACTERIUM
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