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Identification of Pseudomonas Aeruginosa Virulence

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Identification of Pseudomonas Aeruginosa Virulence IDENTIFICATION OF PSEUDOMONAS AERUGINOSA VIRULENCE FACTORS VIA A POPLAR TREE MODEL A Dissertation by CAN ATTILA Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 2008 Major Subject: Chemical Engineering IDENTIFICATION OF PSEUDOMONAS AERUGINOSA VIRULENCE FACTORS VIA A POPLAR TREE MODEL A Dissertation by CAN ATTILA Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved by: Chair of Committee, Thomas K. Wood Committee Members, Arul Jayaraman Jeffrey D. Cirillo Victor M. Ugaz Head of Department, Michael V. Pishko December 2008 Major Subject: Chemical Engineering iii ABSTRACT Identification of Pseudomonas aeruginosa Virulence Factors via a Poplar Tree Model. (December 2008) Can Attila, B.S., Istanbul Technical University, Turkey Chair of Advisory Committee: Dr. Thomas K. Wood Differential gene expression of P. aeruginosa in a rhizosphere biofilm on poplar tree roots was examined in order to identify new virulence factors from this human pathogen. Changes in gene expression for poplar trees contacted with P. aeruginosa was examined as well to identify the response of poplar roots to P. aeruginosa infection. This is the first study of the whole-transcriptome analysis of P. aeruginosa on a plant tree root. The 20 most highly-induced genes of P. aeruginosa were examined for their role in biofilm formation, rhizosphere colonization, barley germination, and poplar tree killing assays. Seven previously uncharacterized virulence genes (PA1385, PA2146, PA2462, PA2463, PA2663, PA4150, and PA4295) were identified. The role of PA2663, a hypothetical protein discovered in the microarrays of P. aeruginosa while killing poplar trees, was examined in further detail. Expression of PA2663 protein increases biofilm formation in P. aeruginosa PAO1 drastically. By complementing the PA2663 mutation in trans and by studying with DNA microarrays and RT-PCR the PA2663 mutant vs. the wild-type strain, PA2663 was confirmed to be related to biofilm formation and was found that it is the first protein to control the psl operon in P. aeruginosa PAO1. Furthermore, PA2663 protein increases pyoverdine synthesis and quorum sensing (QS)- regulated phenotypes. A biofilm formation-related hypothetical protein, PA0939, was identified iv in this study. The effects of indole and 7-hydroxyindole on P. aeruginosa virulence factors were also examined for the first time. Indole and 7HI repressed expression of mexGHI-opmD multidrug efflux pump genes and genes involved in synthesis of QS-regulated virulence factors (pyocyanin, rhamnolipid, PQS, and pyoverdine production). In addition, the effects of an anti-cancer uracil analog, 5-fluorouracil (5-FU) on P. aeruginosa virulence factors and E. coli K-12 biofilm formation were examined. 5-FU repressed biofilm formation, abolished quorum-sensing phenotypes, and reduced virulence in P. aeruginosa. DNA microarray and biofilm studies with 5-FU in E. coli revealed that 5-FU controls biofilm formation through the AriR protein in E. coli K-12 strain. The effects of lsrR and lsrK mutations on E. coli biofilm formation were also examined by flow cell experiments. v DEDICATION To my parents Cevdet and Zeynep Attila vi ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my committee chair Prof. Thomas K. Wood for giving me the opportunity to work on a very challenging project and for his great efforts and guidance with my research. His enthusiasm and pursuit of perfectionism for his work will be a role model throughout my life. I am indebted to my committee members Prof. Arul Jayaraman, Prof. Jeffrey D. Cirillo, and Prof. Victor M. Ugaz for their time and effort to read my dissertation and their splendid suggestions and comments. I would like to thank my colleagues in Dr. Wood’s lab: Dr. Jintae Lee, Prof. Toshinari Maeda, Dr. Rodolfo García-Contreras, Dr. Xuesong Zhang, Dr. Akihiro Ueda, Dr. Chang-Pin Yu, Dr. Younghoon Kim, Dr. Xiaoxue Wang, Dr. Uma Shankar Sagaram, Tarun Bansal, Viviana Sanchez-Torres, Manjunath Hegde, Qun Ma, Andrea Garzon, Seok Hoon Hong, and Brian Liu for their help and suggestions. I would also like to thank my colleagues in Dr. Jayaraman’s lab: Derek Englert, Billy Newton, and Fatih Senocak for their help. I wish to extend my gratitude to our collaborator Suat L. G. Cirillo in Dr. Jeffrey D. Cirillo’s lab. P. aeruginosa guinea pig infection, cytotoxicity, and hemolytic assays would not have been possible without her great work. I would like to thank Prof. Marvin Whiteley and Lauren M. Mashburn-Warren for their assistance with PQS experiments. I would like to thank Prof. Colin Manoil, Prof. Frederick M. Ausubel, and Prof. Robert E. W. Hancock for providing P. aeruginosa transposon mutants. I appreciate the support from the National Institutes of Health (EB003872-01A1) and the National Science Foundation (BES-0331416). vii I am deeply grateful and indebted to my parents Cevdet and Zeynep Attila for their endless support and understanding. I thank my brother Dr. Tan Attila for being an example and a mentor to me. None of this would have been possible without my family. viii TABLE OF CONTENTS Page ABSTRACT .......................................................................................................................... iii DEDICATION ...................................................................................................................... v ACKNOWLEDGEMENTS .................................................................................................. vi TABLE OF CONTENTS ...................................................................................................... viii LIST OF FIGURES ............................................................................................................... xi LIST OF TABLES ................................................................................................................ xiii CHAPTER I INTRODUCTION .......................................................................................... 1 1.1 Background ............................................................................................. 1 1.2 Motivation .............................................................................................. 3 1.3 Research objectives, importance, and novelty ........................................ 5 II LITERATURE REVIEW ............................................................................... 8 2.1 Pseudomonas aeruginosa ....................................................................... 8 2.2 Biofilm formation ................................................................................... 9 2.3 Plant-bacteria interactions ...................................................................... 14 2.4 Quorum sensing ...................................................................................... 24 2.5 Virulence factors of P. aeruginosa ......................................................... 29 2.6 Treatment of P. aeruginosa infections in cystic fibrosis patients ........... 34 III PSEUDOMONAS AERUGINOSA PAO1 VIRULENCE FACTORS AND POPLAR TREE RESPONSE IN RHIZOSPHERE ........................................ 35 3.1 Overview ................................................................................................ 35 3.2 Introduction ............................................................................................ 36 3.3 Results .................................................................................................... 38 3.4 Discussion ............................................................................................... 64 3.5 Experimental procedures ........................................................................ 69 IV PA2663 (PpyR) INCREASES BIOFILM FORMATION IN PSEUDOMONAS AERUGINOSA PAO1 THROUGH THE PSL OPERON AND STIMULATES VIRULENCE AND QUORUM-SENSING PHENOTYPES .......................................................... 79 ix CHAPTER Page 4.1 Overview ................................................................................................ 79 4.2 Introduction ............................................................................................ 80 4.3 Results .................................................................................................... 82 4.4 Discussion ............................................................................................... 101 4.5 Experimental procedures ........................................................................ 103 V INDOLE AND 7-HYDROXYINDOLE DIMINISH PSEUDOMONAS AERUGINOSA VIRULENCE ........................................................................ 112 5.1 Overview ................................................................................................ 112 5.2 Introduction ............................................................................................ 113 5.3 Results .................................................................................................... 115 5.4 Discussion ............................................................................................... 142 5.5 Experimental procedures ........................................................................ 147 VI URACIL INFLUENCES QUORUM SENSING AND BIOFILM FORMATION IN PSEUDOMONAS AERUGINOSA AND FLUOROURACIL IS AN ANTAGONIST ..................................................
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