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Identification and Characterization of Putative Nucleomodulins in Mycobacterium Tuberculosis

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Identification and Characterization of Putative Nucleomodulins in Mycobacterium Tuberculosis IDENTIFICATION AND CHARACTERIZATION OF PUTATIVE NUCLEOMODULINS IN MYCOBACTERIUM TUBERCULOSIS Abstract The nuclear targeting of bacterial proteins that modify host cell gene expression, the so- called nucleomodulins, has emerged as a novel mechanism contributing to virulence of several intracellular pathogens. The goal of this study was to identify nucleomodulins produced by Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and to investigate their role upon infection of the host. We first performed a screening of Mtb genome in search of genes encoding proteins with putative eukaryotic-like nuclear localization signals (NLS). We identified two genes of Mtb, Rv0229c and Rv3876, encoding proteins that are secreted in the medium by Mtb and are localized into the nucleus when expressed in epithelial cells or in human or murine macrophages. The NLSs of these two proteins were identified and found to be essential for their nuclear localization. The gene Rv0229c, a putative RNase, is present only in pathogen species of the Mtb complex and seems to have been recently acquired by horizontal gene transfer (HGT). Rv3876 appears more widely distributed in mycobacteria, and belongs to a chromosomal region encoding proteins of the type VII secretion system ESX1, essential for virulence. Ongoing studies are currently investigating the dynamics of these proteins upon infection of host cells, and their putative role in the modulation of host cell gene expression and Mtb virulence. ii IDENTIFICATION ET CARACTERISATION DE NUCLEOMODULINES PUTATIVES CHEZ LA BACTERIE MYCOBACTERIUM TUBERCULOSIS Résumé Les nucléomodulines sont des protéines produites par des bactéries parasites intracellulaires et qui sont importées dans le noyau des cellules infectées pour y moduler l’expression génique et contribuer ainsi à la virulence de la bactéries. L’identification de nucléomodulines chez plusieurs espèces de bactéries pathogènes a fait émerger ce concept comme une stratégie supplémentaire utilisée par les parasites intracellulaires pour contourner les moyens de défense de l’hôte. Le but de cette thèse était d’identifier et d’analyser d’éventuelles nucléomodulines produites par l’agent étiologique de la tuberculose, la bactérie Mycobacterium tuberculosis (Mtb). Nous avons tout d’abord analysé le génome de Mtb, à la recherche de gènes dont les produits portent des séquences analogues aux séquences de localisation nucléaire des eucaryotes (NLS). Nous avons pu identifier deux gènes de Mtb, Rv0229c et Rv3876, qui codent des protéines sécrétées dans le milieu de culture et qui se localisent dans le noyau lorsqu’elles sont exprimées dans des cellules épithéliales ou dans des macrophages murins ou humains. Les NLS de ces deux protéines ont été identifiées et leur modification abolit la localisation nucléaire dans les cellules eucaryotes. Le gène Rv0229c est trouvé spécifiquement dans le génome des espèces pathogènes du complexe Mtb. Ce gène semble avoir été acquis récemment par l’ancêtre de Mtb, via un transfert génétique horizontal. Rv3876 est plus généralement distribué chez les mycobactéries, et appartient à une région génomique codant un système de sécrétion type VII, ESX1, essentiel pour la virulence de Mtb. Les travaux en cours visent à analyser la dynamique de ces deux protéines au cours de l’infection de macrophages ou de modèles animaux, et leur rôle en tant que modulateurs de l’expression génique des cellules infectées et dans la virulence de Mtb. TABLE OF CONTENTS ABSTRACT ..................................................................................................................... i RÉSUMÉ ...................................................................................................................... ii TABLE OF CONTENTS ................................................................................................... iii LIST OF FIGURES ........................................................................................................ vii LIST OF TABLES ......................................................................................................... viii LIST OF ABBREVIATIONS .......................................................................................... viiii ACKNOWLEDGEMENTS AND GRATITUDE .................................................................. xiii ACKNOWLEDGEMENTS AND AUTHOR ATTRIBUTIONS ................................................ xv CHAPTER 1 INTRODUCTION ......................................................................................... 1 1.1 Tuberculosis ........................................................................................................... 1 I. History of tuberculosis ............................................................................................. 1 II. Epidemiology of tuberculosis ................................................................................. 1 III. Mycobacterium tuberculosis .................................................................................. 2 A. Taxonomy and characteristics ............................................................................ 2 B. Structure of the cell envelope of mycobacteria ................................................. 3 IV. TB treatment and drug resistance ......................................................................... 4 A. Drug resistance in TB today ................................................................................ 5 B. Current and future treatments of MDR- and XDR-TB ......................................... 6 1.2 Host responses to mycobacterium tuberculosis ................................................. 11 I. Immunity to Tuberculosis ...................................................................................... 12 A. Innate immune system during Mtb infection ................................................... 12 B. Adaptive immune system during bacterial infection ........................................ 15 i. Cell-mediated immunity ................................................................................ 15 ii. Humoral immunity and B lymphocyte .......................................................... 17 II. Evasion of the immune response ......................................................................... 18 A. Phagosome maturation .................................................................................... 18 B. Resistance mechanisms .................................................................................... 19 i. ROS and RNS .................................................................................................. 19 ii. Heavy metals: Zinc (Zn)/copper (Cu) ............................................................ 20 iv C. Nutritional mechanisms .................................................................................... 21 D. Cell death: necrosis vs apoptosis ...................................................................... 22 1.3 The concept of nucleomodulins .......................................................................... 24 I. Nuclear transport .................................................................................................. 25 II. Nuclear Localization Signals (NLS) ........................................................................ 26 III. Nucleomodulins ................................................................................................... 27 1.4 Statement of the problem ................................................................................... 31 1.5 Purpose ................................................................................................................ 32 CHAPTER 2 MATERIALS AND METHODS ..................................................................... 33 2.1 In-silico prediction of Mtb proteins targeted to the host cell nucleus ................ 33 2.2 Reagents and chemicals ...................................................................................... 33 I. Commercial Reagents ............................................................................................. 33 II. Enzymes and kits ................................................................................................... 34 III. Oligonucleotides and Sequencing ........................................................................ 34 2.3 Cloning and expression ........................................................................................ 34 I. Amplification of DNA fragments by PCR ................................................................. 34 II. Plasmid constructions ............................................................................................ 35 A. GFP-Fusion plasmid clones ............................................................................... 35 B. Mammalian expression vector constructs ........................................................ 35 C. Generation of plasmid constructs for overexpression ...................................... 35 D. Plasmid constructs for overexpression under inducible promoter .................. 36 E. Site directed mutagenesis ................................................................................. 36 F. Construction of Knockout Mutant of Rv0229c and Rv3876 of Mtb .................. 37 G. Recombineering experiments in Mtb ............................................................... 37 III. Ligation ................................................................................................................. 38 IV. Media
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