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K. Pneumoniae Limiting the Development of New Therapeutic Strategies

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K. Pneumoniae Limiting the Development of New Therapeutic Strategies University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 8-2016 In vivo monitoring of therapeutic efficacy and virulence profile by bioluminescent Klebsiella pneumoniae. Ramy Ameen Fodah University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Part of the Medical Immunology Commons, and the Medical Microbiology Commons Recommended Citation Fodah, Ramy Ameen, "In vivo monitoring of therapeutic efficacy and virulence profile by bioluminescent Klebsiella pneumoniae." (2016). Electronic Theses and Dissertations. Paper 2542. https://doi.org/10.18297/etd/2542 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The nivU ersity of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The nivU ersity of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. IN VIVO MONITORING OF THERAPEUTIC EFFICACY AND VIRULENCE PROFILE BY BIOLUMINESCENT KLEBSIELLA PNEUMONIAE By: Ramy Ameen Fodah B.S. King Saud University, 2005 M.S. University of Louisville, 2012 A Dissertation Submitted to the Faculty of the School of Medicine of the University of Louisville in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Microbiology and Immunology Department of Microbiology and Immunology University of Louisville Louisville, Kentucky August 2016 Copyright 2016 by Ramy Ameen Fodah All rights reserved IN VIVO MONITORING OF THERAPEUTIC EFFICACY AND VIRULENCE PROFILE BY BIOLUMINESCENT KLEBSIELLA PNEUMONIAE By: Ramy Ameen Fodah B.S. King Saud University, 2005 M.S. University of Louisville, 2012 A Dissertation Approved on: June 13, 2016 by the following Dissertation Committee: ____________________________ Dr. Jonathan Warawa (Chair) ____________________________ Dr. Matthew B. Lawrenz ____________________________ Dr. James E. Graham ____________________________ Dr. Michele M. Kosiewicz ____________________________ Dr. David A. Scott ii DEDICATION I would like to dedicate this dissertation to my mother Fatheyah, my father Ameen, my wife Nouf, my son Ahmed, my brothers Ibraheem and Abdulhameed, and to my friends. Your tremendous and continuous support is what made my success in my graduate program possible. .. iii ACKNOWLEDGEMENTS All praises belongs to Almighty Allah, the most beneficent, gracious, and merciful for giving me the opportunity, resolution, and capacity to carry out and complete this dissertation. My deepest gratitude for Dr. Warawa for his continuous support and valuable advises both on the personal and professional levels. I believe that without his involved teaching methods and constructive instructions none of my projects would have come to see the light. I would like to extend my appreciation to my committee members Dr. Matthew B. Lawrenz, Dr. David A. Scott, Dr. Michele M. Kosiewicz, and Dr. James E. Graham for their priceless inputs which helped, guided, and refined my progress in my research projects. Their words of encouragement and support have nourished my growth in my graduate program. I also would like to thank my dear colleagues, the past members of the Warawa laboratory, Jacob Scott, Maria Gutierrez, and Tia Pfeffer whom I had a great pleasure to work with. Tia Pfeffer help me greatly as a friend that I go back to for personal advises and she was a tremendous help for all lab members by preparing and maintaining the supplies needed for conducting our work. Jacob and Maria are great friends that made the time that I have spent in the Warawa laboratory more enjoyable. iv My precious wife Nouf and my dear son Ahemd were the greatest emotional support that I could have ever asked for that made my success in my graduate program possible. Being from a different country, Nouf has been the only family that I have in the United States and she has done a wonderful job supporting me during my graduate study. In addition to being a great wife and friend, Nouf is a wonderful mother to our son Ahmed. My lovely son Ahmed was a blissed addition to our family whom his pleasant laughter and sweet smiles always brings happiness that helped me and my wife survive through any hardships we came across. Thank you Nouf and Ahmed for being part of my life! I would like to send my thanks overseas to the family and friends I have in Saudi Arabia for their motivating words and for their nonstop prayers. My loving parents have always been a great support both emotionally and financially. I would like to thank the Department of Microbiology and Immunology at University of Louisville for giving me the opportunity to be part of this prestigious and successful institution. It is a lovely place where all members of the department are like one big family. I also would like to thank University of Louisville, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), and the Government of Saudi Arabia for their sponsorship and funding that allowed me to pursue my higher education and conduct my research projects. v ABSTRACT IN VIVO MONITORING OF THERAPEUTIC EFFICACY AND VIRULENCE PROFILE BY BIOLUMINESCENT KLEBSIELLA PNEUMONIAE Ramy Ameen Fodah June 13, 2016 Klebsiella pneumoniae causes an acute respiratory infection in human with severe outcomes and high mortality rates even with antibiotic treatment. Even with its critical clinical importance, few virulence systems have been identified for K. pneumoniae limiting the development of new therapeutic strategies. Accordingly, we performed Next Generation sequencing for the strain ATCC 43816, a virulent strain in mouse respiratory disease models, and compared its genomic data with two previously sequenced strains NTUH-K2044 and MGH 78578 for the purpose of identifying genes required for colonizing host lungs. Furthermore, the virulence potential of the three K. pneumoniae strains were tested in a mouse model of pulmonary disease uniquely generated by our group to insure the specific delivery of an inoculum into host lungs allowing for studying diseases associated specifically with the lower respiratory tract. To monitor disease progression noninvasively, a bioluminescent K. pneumoniae strain was engineered which allowed for monitoring meropenem therapeutic efficacy against the bacteria in real time. A transposon mutant library was vi generated in the bioluminescent strain and introduced into mice lungs in order identify critical fitness factors required by K. pneumoniae to survive the selective pressure of host lung. The attenuation of known and potential virulence factors, including capsular polysaccharide (CPS) and type 6 secretion systems (T6SSs), were tested in our lung-specific murine model of respiratory disease. Similar to previous findings, manC capsule mutant was attenuated in our lung-specific disease model whereas for the vgrG T6SSs mutants, only cluster one illustrated some potential attenuation in the host, and future studies will be conducted to confirm these outcomes. K. pneumoniae is thought to be an extracellular pathogen but we have provided the first evidence suggesting that this dogma might not be entirely true by demonstrating the capability of the bacteria to proliferate within cultured macrophages in addition to the ability of a subpopulation of K. pneumoniae to become intracellular within mice lungs. Further studies will need to be conducted to identify the role(s) of the intracellular lifestyle for K. pneumoniae during the pulmonary disease. vii TABLE OF CONTENTS DEDICATION ...................................................................................................... iii ACKNOWLEDGEMENTS ................................................................................... iv ABSTRACT ......................................................................................................... vi LIST OF TABLES .............................................................................................. xiv LIST OF FIGURES ............................................................................................. xv CHAPTER 1 INTRODUCTION............................................................................. 1 1.1 History ............................................................................................................. 1 1.2 Epidemiology .................................................................................................. 2 1.3 Clinical Significance ........................................................................................ 3 1.3.1 K. pneumoniae respiratory infections ....................................................... 4 1.3.1.1 Hospital-acquired pneumonia ............................................................ 4 1.3.1.2 Community-acquired pneumonia ....................................................... 4 1.4 Treatment ....................................................................................................... 6 1.5 Multi-drug Resistance ..................................................................................... 7 1.5.1 Extended-Spectrum Beta-Lactamases ..................................................... 8 1.5.2 Carbapenem Resistance .......................................................................... 9 1.6 Treatment of MDR Klebsiella ........................................................................ 10
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