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Activation and functional studies of the Type VI secretion systems in Pseudomonas aeruginosa Cerith Aeron Jones Department of Life Sciences Imperial College London A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Declaration of Originality The work presented in this thesis is my own, and the contributions of others are duly noted. 2 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 3 Abstract Pseudomonas aeruginosa is a versatile and prevalent opportunistic pathogen. It encodes a large arsenal of pathogenicity factors, and secrets a plethora of proteins using specialised protein secretion systems. The type VI secretion system (T6SS) delivers proteins directly into neighbouring bacteria or eukaryotic cells using a mechanism homologous to the T4 bacteriophage tail spike. Three T6SS are encoded on the P. aeruginosa genome. The study of the H1-T6SS has been facilitated by the fact it can be activated by the manipulation of the RetS/Gac/Rsm regulatory cascade by deletion of retS. However, the precise signals required for activation of this cascade, resulting in H1- T6SS activation, are unknown. This work investigates the role of subinhibitory concentrations of antibiotics in activating the system, and shows that kanamycin is able to induce production of core H1-T6SS components. This activation requires a functional Gac/Rsm cascade, but it is not known if this is due to direct signalling via the cascade, or due to a dominant effect of RsmA repression. The H2-T6SS is characterized in this work. We highlight key differences between the H2-T6SS cluster in PAO1 and PA14, including the presence of additional core T6SS components and putative secreted effectors. A strain is generated in which expression of the PA14 H2-T6SS cluster can be activated and tightly controlled by arabinose inducible promoters. The activity of the promoters is confirmed by the H2-T6SS dependent secretion of Hcp2 specifically upon arabinose induction. We further consider two putative H2-T6SS secreted substrates, VgrG14 and Rhs14. Production of these proteins is observed following arabinose induction, but their secretion is not detected. The Rhs14 protein is characterised, and its possible role as a H2-T6SS dependent effector is discussed. Finally, the H2-T6SS system in PA14 is shown to inhibit the internalisation of P. aeruginosa PA14, in contrast to the previously published observations of the H2-T6SS promoting internalisation of PAO1. 4 Acknowledgements I extend my thanks to Professor Alain Filloux for his guidance and enthusiasm during the time I have spent in his laboratory, and I appreciate his valuable input and support. His mentorship has been both inspiring and challenging, and I am grateful for the excellent apprenticeship I have received during my PhD. Merci Alain! I am of course eternally grateful to my mother, father and sister for their support over the years, and for helping me bounce back following unfortunate circumstances. My PhD would not have been possible without their guidance and positive influence, and I owe them a debt of gratitude for ferrying my belongings around various parts of England and Wales for the past decade! Diolch. Thank you Abdou Hachani for the initial training and guidance at the beginning of my project, and for being a constant source of discussion and ideas. I appreciate the influence that Helga Mikkelsen has had on my PhD, and am thankful for her guidance, inspiration and support. Thanks to Luke Allsopp for his willingness in providing additional data, and to my Undergraduate project student Jack Horlick for his hard work and useful data. Special thanks to Eleni Manoli for always being willing to purify proteins for me, and for being fun to sit next to! I also appreciate the input of Kailyn Hui in keeping everything running smoothly in the lab, and thank Joana, Daniela, Nadine and Sara for making the Filloux lab such a nice place to work! I thank my wonderful colleague Heather Combe for careful reading of this manuscript and for her own special style of support and humour during my time at Imperial. Thanks to Sarah Tomlinson for fun adventures away from the lab which helped keep me motivated, and for introducing me to Poppies! My PhD would have been impossible without the constant support of Allie Shaw, Abbie, and Lisa, and I especially thank Allie for useful discussions on work and life, and for sharing many fajiwraps and random adventures in London and beyond! It has been great fun, and transient friendships should always get the seal of disapproval! Diolch o galon i Rhian Williams am wrando I fi yn cwyno am oriau, ac am dy help yn hybu fi i gario mlaen a chwpla lan! Diolch hefyd i’r merched (Sioned, Llinos, Llio, Catrin a Manon) am yr hwyl gafon ni ar ein anturon yn Llundain! Joio! 5 Table of Contents Chapter 1 Introduction ................................................................................. 14 1.1 Pseudomonas aeruginosa ........................................................................................................... 14 1.2 P. aeruginosa the opportunistic pathogen ................................................................................. 16 1.2.1 Opportunistic infections ...................................................................................................... 16 1.2.2 P. aeruginosa infections and Cystic Fibrosis ....................................................................... 17 1.2.3 Antibiotic resistance ............................................................................................................ 18 1.3 P. aeruginosa pathogenicity factors: cell associated .................................................................. 20 1.4 P. aeruginosa biofilm formation ................................................................................................. 23 1.4.1 Biofilm characteristics ......................................................................................................... 23 1.4.2 Components of the biofilm matrix ...................................................................................... 24 1.4.3 The biofilm development cycle ........................................................................................... 27 1.4.4 Antibiotic resistance in P. aeruginosa biofilms ................................................................... 32 1.5 Extracellular pathogenicity factors ............................................................................................. 33 1.6 P. aeruginosa pathogenicity factors: Secreted proteins ............................................................ 36 1.6.1 Inner Membrane Translocation .......................................................................................... 38 1.6.2 The Type I Secretion System (T1SS) .................................................................................... 42 1.6.3 The Type II Secretion System (T2SS) ................................................................................... 44 1.6.4 The Type III Secretion System (T3SS) .................................................................................. 50 1.6.5 The Type IV Secretion System (T4SS) .................................................................................. 57 1.6.6 The Type V Secretion System (T5SS) ................................................................................... 57 1.7 The Type VI Secretion System (T6SS) ......................................................................................... 61 1.7.1 Phage-like Components of the T6SS ................................................................................... 61 1.7.2 Other components of the T6SS ........................................................................................... 66 1.7.3 T6SS toxin delivery .............................................................................................................. 68 1.7.4 T6SS effectors targeted into eukaryotic cells ...................................................................... 70 1.7.5 Bacterial targeted T6SS toxins............................................................................................. 74 1.7.6 Regulation of T6SS ............................................................................................................... 82 1.7.7 Dynamics of the P. aeruginosa H1-T6SS ............................................................................. 85 1.8 Global Regulation of Pathogenicity in P. aeruginosa ................................................................. 87 1.8.1 Quorum Sensing .................................................................................................................. 88 1.8.2 cAMP ................................................................................................................................... 94 1.8.3 The Stringent Response....................................................................................................... 95 1.8.4 c-di-GMP .............................................................................................................................
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