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View / Download 4.8 Mb Aminopeptidase-Dependent Modulation of Bacterial Biofilms by Pseudomonas aeruginosa Outer Membrane Vesicles by Caitlin Noel Esoda Department of Molecular Genetics and Microbiology Duke University Date:_______________________ Approved: ___________________________ Margarethe Kuehn, Supervisor ___________________________ David Tobin ___________________________ Dennis Ko ___________________________ Mari Shinohara Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Molecular Genetics and Microbiology in the Graduate School of Duke University 2019 i v ABSTRACT Aminopeptidase-Dependent Modulation of Bacterial Biofilms by Pseudomonas aeruginosa Outer Membrane Vesicles by Caitlin Noel Esoda Department of Molecular Genetics and Microbiology Duke University Date:_______________________ Approved: ___________________________ Margarethe Kuehn, Supervisor ___________________________ David Tobin ___________________________ Dennis Ko ___________________________ Mari Shinohara An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Molecular Genetics and Microbiology in the Graduate School of Duke University 2019 i v Copyright by Caitlin Noel Esoda 2019 Abstract Pseudomonas aeruginosa, known as one of the leading causes of morbidity and mortality in cystic fibrosis (CF) patients, secretes a variety of virulence-associated proteases. These enzymes have been shown to contribute significantly to P. aeruginosa pathogenesis and biofilm formation in the chronic colonization of CF patient lungs, as well as playing a role in infections of the cornea, burn wounds and chronic wounds. Our lab has previously characterized a secreted P. aeruginosa peptidase, PaAP, that is highly expressed in chronic CF isolates. This leucine aminopeptidase is also highly expressed during infection and in biofilms, and it associates with bacterial outer membrane vesicles (OMVs), structures known for their contribution to virulence mechanisms in a variety of Gram-negative species and one of the major components of the biofilm matrix. With this in mind, we hypothesized that PaAP may play a role in P. aeruginosa biofilm formation. Using a lung epithelial cell/bacterial biofilm coculture model, we show that PaAP deletion in a clinical P. aeruginosa background alters biofilm microcolony composition to increase cellular density, while decreasing matrix polysaccharide content and resistance to the antibiotic colistin. We recreate this phenotype using a pellicle biofilm model, in which bacteria are grown statically at the culture air-liquid interface, demonstrating that these phenotypes are not dependent on the coculture host cell substrate. We additionally show that OMVs from PaAP expressing strains, but not PaAP alone or in combination with iv PaAP deletion strain-derived OMVs, could complement this phenotype. Finally, we found that OMVs from PaAP-expressing strains cause protease-mediated biofilm detachment, leading to changes in matrix and colony composition. OMVs mediated the detachment of biofilms formed by both non-self P. aeruginosa strains and Klebsiella pneumoniae, another respiratory pathogen, showing that this process may also be relevant in polymicrobial communities and acts on non-P. aeruginosa derived substrates. Our findings represent novel roles for OMVs and the PaAP aminopeptidase in the modulation of bacterial biofilm architecture. v Dedication To my wonderful family and friends. Without their love and support this never would have been possible. vi Contents Abstract ......................................................................................................................................... iv List of Tables ................................................................................................................................ xii List of Figures ............................................................................................................................ xiii Acknowledgements .................................................................................................................... xv 1. Introduction ............................................................................................................................. 16 1.1 Outer membrane vesicles ......................................................................................... 16 1.1.1 Prevalence of OMVs .................................................................................................. 17 1.1.2 Outer membrane vesicle formation and composition .......................................... 19 1.1.3 Vesicle interactions with host cells and modulation of immune responses ..... 23 1.1.4 Other functions of OMVs ......................................................................................... 28 1.1.4.1 Resistance to antibiotics, phage, and stress .................................................... 28 1.1.4.2 Interspecies interactions .................................................................................... 30 1.1.4.3 Biofilm formation ............................................................................................... 31 1.2 Model organism: Pseudomonas aeruginosa ............................................................... 31 1.2.1 P. aeruginosa infections .............................................................................................. 32 1.2.2 P. aeruginosa as a model organism for biofilm formation .................................... 34 1.2.3 P. aeruginosa quorum sensing .................................................................................. 34 1.2.4 P. aeruginosa virulence .............................................................................................. 37 1.2.4.1 P. aeruginosa proteases ..................................................................................... 37 1.2.4.2 Other P. aeruginosa virulence factors ............................................................... 39 vii 1.2.5 P. aeruginosa OMVs ................................................................................................... 41 1.2.5.1 P. aeruginosa OMV biogenesis .......................................................................... 41 1.2.5.2 Composition of P. aeruginosa OMVs ................................................................ 43 1.2.5.3 P. aeruginosa OMV functions and interaction with host cells ...................... 44 1.3 Biofilm formation ........................................................................................................... 45 1.3.1 Stages of biofilm maturation .................................................................................... 45 1.3.2 The biofilm matrix ..................................................................................................... 48 1.3.3 OMVs and biofilms ................................................................................................... 51 1.3.4 Models for studying biofilm formation .................................................................. 52 1.4 Bacterial aminopeptidases ............................................................................................. 54 1.4.1 Description and classification of aminopeptidases .............................................. 54 1.4.2 Traditional physiological roles of bacterial aminopeptidases ............................ 55 1.4.3 Bacterial protease immune-modulating and moonlighting functions .............. 56 1.5 P. aeruginosa leucine aminopeptidase (PaAP)........................................................... 58 1.5.1 PaAP identification and classification .................................................................... 60 1.5.2 PaAP expression, secretion, and activation ........................................................... 61 1.5.3 PaAP identification in P. aeruginosa OMVs ............................................................ 65 1.5.4 PaAP’s role in P. aeruginosa infection and biofilm formation ............................. 67 2. P. aeruginosa leucine aminopeptidase mediates early biofilm formation and affects matrix composition ..................................................................................................................... 70 2.1 Summary .......................................................................................................................... 70 2.2 Introduction ..................................................................................................................... 71 viii 2.3 Development of a coculture model to study the effects of PaAP on biofilm formation under infection-like conditions ........................................................................ 73 2.3.1 Confirmation of cocultures colonies as biofilms ................................................... 76 2.4 PaAP deletion increases biomass and cellular organization in coculture biofilms ................................................................................................................................................. 78 2.5 Differences between wild type and ∆PaAP biofilms develop late in the observed time course ............................................................................................................................ 82 2.6 ∆PaAP biofilm matrices contain less of the exopolysaccharide Psl and display increased susceptibility to colistin ....................................................................................
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