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The Role of Outer Membrane Proteins of Porphyromonas Gingivalis in Host-Pathogen Interactions Kathryn Lucy Naylor

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The Role of Outer Membrane Proteins of Porphyromonas Gingivalis in Host-Pathogen Interactions Kathryn Lucy Naylor The Role of Outer Membrane Proteins of Porphyromonas gingivalis in Host-Pathogen Interactions By: Kathryn Lucy Naylor A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy The University of Sheffield Faculty of Medicine, Dentistry and Health School of Clinical Dentistry 23 / 08 / 2016 Summary The keystone periodontal pathogen, P. gingivalis, is a Gram-negative oral anaerobe that is strongly implicated as the prime etiological agent in the initiation and progression of periodontal disease. P. gingivalis contains a plethora of virulence factors, including fimbriae, proteases, lipopolysaccharides and outer membrane proteins that contribute to the pathogenesis of the disease. The bacterium also displays the ability to interact with host cells through the adherence and invasion both in vitro and in vivo. In this thesis new light has been shed on the role of the heterotrimeric outer membrane protein A (OmpA). Through the creation of ompA mutants and recombinant complementation plasmids, alongside the use of standard antibiotic protection assays in an oral epithelial cell line, this research has demonstrated the importance of OmpA, specifically the OmpA2 subunit, in the invasion of the host and in the ability of the bacteria to form biofilms. Structural analysis of the protein identified extracellular loops, which when synthetic versions were applied to host cells, demonstrated successful interruption of wild-type P. gingivalis adherence and invasion of the host, indicating a direct interaction of OmpA2 with oral epithelial cells. In particular, this research demonstrates that OmpA2-loop 4 plays an important role in the interaction with the host through significantly increased binding to host cells when applied to fluorescent latex beads. This work also characterised the putative periplasmic chaperone protein OmpH, identifying potential proteins that act as clients to this chaperone, including OmpA. Through the creation of an ompH1H2 knock out mutant, enzymatic analysis of various virulence factors was assessed, demonstrating a loss of gingipain activity, whilst also identifying a loss of membrane stability through the observation of an increase in outer membrane vesicle formation. Evidence is also presented for the role of OmpH protein in chaperoning OmpA across the periplasm to the outer membrane and this work has opened up the potential for novel work identifying other clients of this chaperone system. Overall, the work in this thesis has demonstrated that the OmpA protein, specifically OmpA2, is directly involved in the interaction with host oral epithelial cells and in biofilm formation, specifically demonstrating the direct role of the extracellular surface loops in this interaction. This work also hypothesises a role for the OmpH protein in chaperoning outer membrane proteins, with the identification of potential clients, such as OmpA and the gingipains. Finally, this work has developed an improved mutagenesis technique for the creation of P. gingivalis mutants based on a modified natural competence method. 1 Acknowledgments First and foremost, I would like to thank The University of Sheffield for both providing me with this opportunity as well as the funding to go with it. Also thanks are given to the external funding from the Oral and Dental Research Trust, and the Microbiology Society. Special thanks and appreciation go to my supervisor, Dr Graham Stafford for his continuous support, encouragement and motivation. I have greatly benefited from his advice, guidance and unfaltering confidence in me, without which this work would not have been possible. I would also like to thank my supporting supervisors, Professor Ian Douglas and Dr Craig Murdoch, for the academic help and support. I would like to also give thanks to the kind donations of antibodies from Dr Keiji Nagano and Professor Ashu Sharma. Thanks go to the technical support staff, Jason Heath and Brenka McCabe, who work tirelessly behind the scenes and without whom the lab would be absolute chaos. Thank you to you both for providing a friendly environment that has been a pleasure to work in. Also thanks to David Thompson for your technical expertise in electron microscopy. I would like to thank particularly the current and previous folk of the Dental School and MBB for all the good times and friendship throughout my time here. Special thanks to Genevieve, Ellie, Caroline, Viki, Sarah, Andy, Mark, Laura and Serina who have provided me with all the encouragement and support, multiple delicious dinners with copious amounts of wine and chocolate to get me through the tough times. I’m sure together, we have managed to keep many Prosecco vineyards afloat throughout the years. You guys are the best! I am so grateful for my amazing family during this time, to listen to me babble on about science things that go above their heads, providing excellent words of encouragement when I whinge about insoluble proteins and failed Western blots even if they don’t understand what these are. And I can’t forget to say thanks to the Bank of Mum and Dad for the financial support when my PhD funding finished but my experiments hadn’t! Finally and most importantly, I would like to mention my favourites, Liz, Charlotte and Aidan. There aren’t words adequate enough to describe how much you guys have meant to me during this PhD and thesis writing (and all the years before!), for all the love and support you guys have given me through all of the good times and the bad. As much as I hate using the word, I literally could not have done this without you guys. Much love. 2 List of Abbreviations A-LPS – A-antigen lipopolysaccharide Amp – ampicillin APS – ammonium persulphate ATCC – American Type Culture Collection BA – blood agar plates BHI – brain heart infusion BSA – bovine serum albumin CFU – colony forming units CIP – calf alkaline phosphatase c-JNK – c-Jun N-terminal kinase CPS - capsular polysaccharide CR3 – complement receptor 3 CTD – C-terminal domain CY – cytoplasm DKSFM – defined keratinocyte serum free media DMEM – Dulbecco’s modified Eagle’s medium DTT - dithiothreitol EC - extracellular ECM – extracellular matrix eDNA – extracellular DNA EDTA – ethlenediaminetetraacetic acid EPEC – enteropathogenic E. coli EPS – extracellular polysaccharide Ery – Erythromycin FA – fastidious anaerobic agar FAK – focal adhesion kinase 3 FBS – foetal bovine serum GST – Glutathione-S-transferase HAART – highly active antiretroviral therapy HagA – Haemagglutinin A IL – interleukin IM – inner membrane IMAC – immobilised metal-ion affinity chromatography IPTG – isopropyl β-D-1-thiogalactopyranoside Kgp – Lysine-specific gingipain LB – Luria broth LPS – lipopolysaccharide MBP – maltose binding protein MOI – multiplicity of infection Msp – major outer sheath protein mTOR – mammalian target of rapamycin MTP – microtitre plate MUNANAC – 2’-(4-Methylumbelliferyl)-α-D-N-acetylneuraminic acid NAM – N-acetylmuramic acid NC - nitrocellulose NETs – neutrophil extracellular traps NUG – necrotising ulcerative gingivitis NUP – necrotising ulcerative periodontitis OD – optical density O-LPS – O-antigen lipopolysaccharide OMP – outer membrane protein OmpA – outer membrane protein A OmpH – outer membrane protein H 4 OMVs – outer membrane vesicles OppA – oligopeptide transporter P - pellet PADs –peptidyl-arginine deaminase PAMPs – pathogen-associated molecular patterns PBS – phosphate buffered saline PCR – polymerase chain reaction PG - peptidoglycan PorSS – Por secretion system PP - periplasm PPADs – P. gingivalis peptidyl-arginine deaminase PRR – pattern recognition receptor Rgp – Arginine-specific gingipain S - Secreted (gingipains) S - Soluble (dialysis) S-layer – surface layer SD – standard deviation SDS-PAGE – Sodium dodecyl sulphate polyacrylamide gel electrophoresis SEM – standard error of the mean Skp – Seventeen kilodalton protein T9SS – Type 9 secretion system (PorSS) TAE – tris-acetate EDTA TEM – transmission electron microscopy Tet – tetracycline Tir – translocated intimin receptor TLCK – N-α-tosyl-L-phenylalanine chloromethyl ketone TLRs – Toll-like Receptors 5 TNF – Tumour necrosis factor TO – thiazole orange TPCK – N-α-p-tosyl-L-lysine chloromethyl ketone TRPS – tuneable Resistance Pulse Sensing TRX – thioredoxin TTSS – Type 3 secretion system Ub - ubiquitin WC – whole cell WGA – wheat germ agglutinin WHO – World Health Organisation WT – wild-type 6 Table of contents Summary .................................................................................................................................. 1 Acknowledgments .................................................................................................................... 2 List of Abbreviations ................................................................................................................ 3 Table of contents ..................................................................................................................... 7 List of Figures ......................................................................................................................... 12 List of Tables .......................................................................................................................... 15 Chapter 1 ................................................................................................................................ 16 Introduction and Literature Review ....................................................................................... 16 1.1 Overview
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