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Proteome Analyses of Host Membranes Modified by Intracellular Salmonella Enterica Typhimurium

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Proteome Analyses of Host Membranes Modified by Intracellular Salmonella Enterica Typhimurium Proteome analyses of host membranes modified by intracellular Salmonella enterica Typhimurium D i s s e r t a t i o n zur Erlangung des Grades “Doctor rerum naturalium” (Dr. rer. nat.) des Fachbereichs Biologie/Chemie an der Universität Osnabrück vorgelegt von Stephanie Vorwerk aus Bielefeld Osnabrück, März 2016 Hauptberichterstatter: Prof. Dr. Michael Hensel 2. Berichterstatter: Prof. Dr. Hubert Hilbi Weitere Mitglieder der Prüfungskommission: Prof. Dr. Karlheinz Altendorf Dr. Heiko Harten „Zwei Dinge sind zu unserer Arbeit nötig: Unermüdliche Ausdauer und die Bereitschaft, etwas, in das man viel Zeit und Arbeit gesteckt hat, wieder wegzuwerfen.“ Albert Einstein Für meine Eltern I Table of Content I INTRODUCTION............................................................................................................. 1 I.1 Home inside the host cell – the endosomal system ..................................... 1 I.1.1 Rab GTPases as master regulators ............................................................ 3 I.1.2 Regulation of the endocytic pathway........................................................... 5 I.1.3 Phagocytosis .............................................................................................. 8 I.2 Lifestyles of intracellular pathogens .............................................................. 9 I.2.1 Escape from the phagosome – cytosolic lifestyle .......................................11 I.2.2 Modification of the phagosome ─ vacuolar lifestyle ....................................13 I.3 Salmonella as model organisms ...................................................................17 I.3.1 Pathogenesis .............................................................................................17 I.3.2 Cellular aspects of Salmonella’s pathogenesis ..........................................18 I.4 Proteomics of intracellular pathogens ..........................................................24 I.4.1 Proteomics of Salmonella and the host ......................................................26 I.5 Aim of this work .............................................................................................27 II RESULTS AND PUBLICATIONS ................................................................................. 29 II.1 Proteomes of host cell membranes modified by intracellular activities of Salmonella enterica ........................................................................................29 II.2 How Salmonella modifies its killer – proteomic analysis of Salmonella- modified membranes in macrophages .........................................................42 II.2.1 Abstract .....................................................................................................42 II.2.2 Introduction ................................................................................................42 II.2.3 Results ......................................................................................................45 II.2.4 Discussion .................................................................................................55 II.2.5 Material and Methods ................................................................................64 II.2.6 Acknowledgements ....................................................................................68 II.2.7 Supplementary Materials ...........................................................................69 II.3 The SPI2-T3SS effector SseJ based Salmonella-modified membrane proteome .........................................................................................................70 II.3.1 Abstract .....................................................................................................70 II.3.2 Introduction ................................................................................................71 II.3.3 Results ......................................................................................................73 II.3.4 Discussion .................................................................................................80 II.3.5 Material and Methods ................................................................................84 II.3.6 Acknowledgment .......................................................................................89 II II.3.7 Supplementary Materials ........................................................................... 89 II.4 Contributions to Co-authors ......................................................................... 90 III DISCUSSION ............................................................................................................... 91 III.1 Proteomics as suitable tool for host-pathogen interaction analysis .......... 91 III.2 The Salmonella-modified membrane proteome ......................................... 100 III.3 Comparison of PCV proteomes .................................................................. 104 III.3.1 Actin cytoskeletal proteins ....................................................................... 106 III.3.2 Protein folding ......................................................................................... 109 III.3.3 Protein sorting ......................................................................................... 111 III.4 Conclusion and Outlook .............................................................................. 116 IV SUMMARY/ZUSAMMENFASSUNG .......................................................................... 119 IV.1 Summary ...................................................................................................... 119 IV.2 Zusammenfassung ...................................................................................... 120 V REFERENCES ........................................................................................................... 122 VI APPENDIX ................................................................................................................. 163 VII LIST OF ABBREVIATIONS ....................................................................................... 165 VIII LIST OF FIGURES ..................................................................................................... 168 IX LIST OF TABLES ...................................................................................................... 170 X CURRICULUM VITAE ................................................................................................ 171 XI LIST OF PUBLICATIONS .......................................................................................... 173 XII DANKSAGUNG ......................................................................................................... 174 XIII ERKLÄRUNG ÜBER DIE EIGENSTÄNDIGKEIT DER ERBRACHTEN WISSENSCHAFTLICHEN LEISTUNG ....................................................................... 176 Introduction 1 I Introduction One of the leading causes of morbidity and mortality worldwide are infectious diseases (World Health Organization, 2008). Bacterial pathogens play a key role and are still a public health threat, especially considering the increasing antibiotic resistance (World Health Organization, 2014). It is necessary to gain a deeper understanding of pathogen- host interactions to identify new targets for therapies on molecular and cellular levels (Briken, 2008). In particular the complex host/pathogen relations of intracellular bacterial pathogens in eukaryotic cells are of special interest (Bumann, 2010). These microorganisms have evolved strategies to manipulate host membranes and host trafficking system to create a replication niche and evade the host immune response (Alonso and Garcia-del Portillo, 2004). Thus the understanding of pathogen’s modification of the host deepen the knowledge of the basic cellular processes (Sherwood and Roy, 2013). This work focuses on the foodborne bacterial pathogen Salmonella enterica subsp. enterica serovar Typhimurium that is used as model system for S. Typhi infections. S. Typhimurium is able to create a unique replicative niche. The host endosomal system is remodelled by forming a network of tubular, membranous structures connected with the Salmonella-containing vacuole (SCV). To understand intracellular survival and replication strategies of bacterial pathogens such as S. Typhimurium, a deep knowledge about the cellular environment is necessary to figure out how the endosomal system is manipulated by intracellular bacteria. In the following paragraphs the endosomal system, important intracellular bacterial pathogens and in particular S. Typhimurium will be described in more detail. I.1 Home inside the host cell – the endosomal system The host cell is a complex structure as habitat for intracellular bacterial pathogens. It contains several membranous organelles which are connected by an extensive vesicle transport system which can be divided in the secretory and endocytic pathway. An overview of compartments, considering the endocytic and secretory system, with their pathways and marker proteins is shown in Figure I-1. 2 Introduction Figure I-1: Interaction of main compartments of endocytic and secretory pathways. In the endocytic pathway (blue arrows) cargo is incorporated in vesicles derived from plasma membrane and is transported to early endosomes and via late endosomes to lysosomes. Proteins and lipids are delivered from the endoplasmic reticulum (ER) to the plasma membrane or to lysosomes in the secretory pathways (green arrows). Components of the early
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