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The Role of Prophages in Pseudomonas Aeruginosa

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The Role of Prophages in Pseudomonas Aeruginosa The role of prophages in Pseudomonas aeruginosa Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Emily Victoria Davies July 2015 To Gran, the kindest and wisest woman I have ever known. You always encouraged me to go to university and I’m so glad that I did. Abstract Pseudomonas aeruginosa is a common opportunistic respiratory pathogen of individuals with cystic fibrosis (CF), capable of establishing chronic infections in which the bacterial population undergoes extensive phenotypic and genetic diversification. The Liverpool Epidemic Strain (LES) is a widespread hypervirulent and transmissible strain that is capable of superinfection and is linked to increased morbidity and mortality, relative to other P. aeruginosa strains. The LES has six prophages (LESφ1-6) within its genome, of which three are essential to the competitiveness of this strain. Temperate bacteriophages are incredibly common in bacterial pathogens and can contribute to bacterial fitness and virulence through the carriage of additional genes or modification of existing bacterial genes, lysis of competitors, or by conferring resistance to phage superinfection. Furthermore, the LES phages are detected at high levels in the CF lungs and have been implicated in controlling bacterial densities. The aims of this study were to (i) further characterise the LES phages and their induction, (ii) determine the extent to which the LES phages contribute to bacterial phenotypic and (iii) genetic diversification and (iv) determine how the LES phages affect host competitiveness, using a variety of in vitro and in vivo infection models. LES phages are continuously produced by spontaneous lysis and this study found that environmental factors that are common to the CF lung, such as oxidative stress, pharmaceutical chelating agents and antibiotics, can alter phage production by clinical LES isolates. Characterisation of the phages highlighted differences between the phages with regards to their lytic cycles and ability to propagate in different environments. P. aeruginosa undergoes extensive phenotypic diversification in an artificial sputum model (ASM) of infection, similar to that observed in chronic CF infections. Hypermutability, loss of motility and auxotrophy were phenotypes observed in bacteria evolved for approximately 240 bacterial generations in ASM in the presence and absence of the LES phages. However, the LES phages accelerated this process; loss of twitching motility occured earlier in populations evolved in the presence of phages. Sequencing of evolved populations revealed a high level of genetic diversification, with genes involved in motility, quorum sensing and genetic regulation experiencing loss of function mutations in parallel populations. In phage treated populations, LESφ4 had disruptively integrated into motility and quorum sensing genes, suggesting that temperate phages can provide an alternative (and quicker) route to adaptation. LES prophage carriage is important for bacterial competitiveness; PAO1 LES Phage Lysogens (PLPLs) successfully invaded a phage-susceptible population in vitro from when initially rare. Strain invasiveness was dependent on the LES prophage; LESφ4 lysogens were more invasive than PLPLφ2 or PLPLφ3, whereas carriage of all three prophages accelerated bacterial invasion. PLPLφtriple could also invade a susceptible competitor population in a rat model of chronic lung infection, although not as successfully as in vitro. These data suggest that prophage carriage is important for LES competitiveness and that phage- mediated lysis of phage-susceptible competitors may explain why LES is adept at superinfection. The study indicates that the LES phages are important drivers of bacterial diversification and evolution and confer a competitive advantage to their bacterial host. This may help explain why the LES is so successful, and the high prevalence of polylysogeny in bacterial pathogens. i Declaration This thesis is the result of my own work. The material presented here has not been presented and is not being presented, either wholly or in part for any other degree or qualification. Some of the technical procedures were carried out in collaboration with other people and reference has been made to specific data from other colleagues where appropriate. This project was co-supervised by Professors Steve Paterson, Craig Winstanley and Aras Kadioglu at the University of Liverpool, and Professor Michael Brockhurst at the University of York. All experimental work was carried out in the research laboratory of Professor Craig Winstanley at the Institute of Infection and Global Health, University of Liverpool. Emily Davies ii Acknowledgements I would like to thank all my supervisors on this project: Professors Craig Winstanley, Mike Brockhurst, Steve Paterson and Aras Kadioglu. They have always been ready and willing to answer any questions I may have, and their insightful discussions have been invaluable in keeping me on track. I am especially indebted to Craig, who has been a constant source of support and encouragement over the last few years (especially during the writing of this thesis) and keeps us all entertained in lab meetings with his witty comments. Some of the work in this thesis would not have been possible without the help of others. The Winstanley lab group have been a constant friendly source of help and advice. The bioinformatic analysis and expertise provided by Dr. Sam Haldenby has been invaluable, and a special acknowledgement goes to Dr. Chloe James who was a brilliant (and very patient) mentor at the start of my PhD and always has a smile on her face. Thanks also to Professor Roger Levesque at Laval University who hosted me in his laboratory for two months, and to Dr. Irena Kukavica-Ibrulj who was an excellent teacher in the lab and helped me to settle in, taking me out for the most amazing Quebecois ice- cream. In addition, I would like to thank the Society for General Microbiology for the research grant that enabled me to visit Quebec, without which a large part of this study would not have been possible, as well as the Medical Research Council and University of Liverpool, who co-funded this project. I would like to express my gratitude to all of those in IGH. There is always someone willing to help or share knowledge if you’re struggling. Thanks especially to those who frequent the AJ for the welcome distraction from the daily grind of the lab. I am so grateful to my family, who have always supported me and encouraged me to do whatever I wanted to do, and to my in-laws for moral support. Last but not least, I express my heartfelt appreciation to my husband Robin who has always been by side and has never complained. You have listened to countless practice presentations and proofread numerous documents over the years and now know more about phages than any other teacher I know! iii Table of Contents Abstract ........................................................................................................................ i Declaration .................................................................................................................. ii Acknowledgements .................................................................................................... iii Table of Contents ...................................................................................................... iv Table of Figures ....................................................................................................... xiv Table of Tables ...................................................................................................... xviii Abbreviations ........................................................................................................... xix Chapter 1 - General Introduction ............................................................................. 1 1.1 Microbial infections in cystic fibrosis ........................................................... 1 1.1.1 Cystic Fibrosis (CF) ............................................................................... 1 1.1.1.1 Oxidative stress ............................................................................................ 2 1.1.2 Common CF pathogens .......................................................................... 3 1.2 Pseudomonas aeruginosa .............................................................................. 4 1.2.1 Virulence in CF ...................................................................................... 5 1.2.2 Antimicrobial therapy of P. aeruginosa infection in CF ....................... 6 1.2.3 Infection and transmission in CF ........................................................... 7 1.2.4 Genetics of P. aeruginosa ...................................................................... 8 1.2.4.1 DNA mismatch repair (MMR) system ....................................................... 10 1.2.5 Cell surface structures .......................................................................... 11 1.2.5.1 Pili .............................................................................................................. 11 1.2.5.2 Flagella ....................................................................................................... 14 1.2.6 Motility ................................................................................................. 15 1.2.6.1 Swarming...................................................................................................
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