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A Dissertation Entitled Characterization of a Novel A Dissertation entitled Characterization of a novel Francisella tularensis Virulence Factor Involved in Cell Wall Repair by Briana Collette Zellner Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences ___________________________________________ Jason Huntley, Ph.D., Major Advisor ___________________________________________ R. Mark Wooten, Ph.D., Committee Member ___________________________________________ Jyl Matson, Ph.D., Committee Member ___________________________________________ Robert Blumenthal, Ph.D. Committee Member ___________________________________________ R. Travis Taylor, Ph.D., Committee Member ___________________________________________ Cyndee Gruden, PhD, Dean College of Graduate Studies The University of Toledo December 2019 © 2019 Briana Collette Zellner This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Characterization of a Novel Francisella tularensis Virulence Factor Involved in Cell Wall Repair by Briana Collette Zellner Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences The University of Toledo December 2019 Francisella tularensis, the causative agent of tularemia, is one of the most dangerous bacterial pathogens known. F. tularensis has a low infectious dose, is easily aerosolized, and induces high morbidity and mortality; thus, it has been designated as a Tier 1 Select Agent. Studies to identify and characterize F. tularensis envelope proteins are important to help understand the molecular mechanisms by which F. tularensis, and other intracellular pathogens cause disease, and may lead to the development of new therapeutics. In previous studies, we demonstrated that the F. tularensis disulfide bond formation protein ortholog, DsbA, is required for virulence and, more importantly, identified >50 DsbA substrates, half of which are annotated as hypothetical proteins or proteins with unknown functions. In the current study, we selected one of these unstudied DsbA substrates, FTL1678, for detailed analysis. Using bioinformatics, FTL1678 was found to contain a putative L,D-carboxypeptidase A (LdcA) domain, indicating a potential role in peptidoglycan (PG) remodeling, which likely is required for the intracellular lifestyle of F. tularensis. Unlike prototypic LdcA homologs, F. tularensis LdcA does not localize to the cytoplasm. An FTL1678 mutant was completely iii attenuated in a mouse pulmonary infection model, with decreased lung colonization and inability to disseminate to livers or spleens. Mutant attenuation was confirmed through complementation with wild-type (WT) FTL1678, as well as the Campylobacter jejuni LdcA homolog Pgp2, and both fully-restored virulence to WT levels. Importantly, immunization with this mutant provided significant protection against pulmonary challenge with fully-virulent F. tularensis strain SchuS4 (in the BSL3). Membrane integrity testing revealed differences in cell wall permeability between WT F. tularensis Live Vaccine Strain (LVS) and ΔFTL1678 and electron microscopy analysis of ΔFTL1678 showed increased outer membrane thickness. In addition, through enzymatic assays, FTL1678 was shown to have L,D-carboxypeptidase and L,D-endopeptidase activities, cleaving peptidoglycan pentapeptides to tetrapeptides and tripeptides. These studies have revealed a new F. tularensis virulence factor and have highlighted the importance of the F. tularensis envelope in protecting the bacterium during infection. iv This work is dedicated to my parents, Kent and Kathy Zellner. Your continued love and support over the past four and a half years have been a crucial component of my success. You have always been my biggest cheerleaders in life, even when I wasn’t sure of myself, and I can’t thank you enough for always being there for me. v Acknowledgements I would first like to thank my advisor, Dr. Jason F. Huntley for all of his support and guidance. I consider myself very lucky to have had the privilege of working in his laboratory for the past four years. My time in the Huntley lab, and his mentorship has made me a better scientist not only in a technical sense, but also as an independent and critical thinker. I would also like to thank my committee members, Drs. Jyl Matson, R. Mark Wooten, Robert Blumenthal, and R. Travis Taylor, for all their advice on my project over the years and for being available and willing to help me whenever I needed it. Next, I would like to thank the past and current members of the Huntley lab, Dr. Wilma Wu, Nicole Bearss, Alison Brandel, Kayla Uveges, Nick Mitchell, Brenden Tully, and Alex McCartney for all your help and friendship through this process. I wouldn’t have made it through without you all. Finally, I would like to thank all of our collaborators, Dr. Dominique Mengin- Lecreulx (University of Paris), Drs. Joe Dillard and Ryan Schaub (University of Wisconsin-Madison), Dr. Erin Gaynor (University of British Columbia), and Drs. William Gunning and Robert Booth (University of Toledo) for their contributions to my dissertation research. vi Table of Contents Abstract ......................................................................................................................... iii Acknowledgements ........................................................................................................ vi Table of Contents ..........................................................................................................vii List of Tables.................................................................................................................xii List of Figures ............................................................................................................. xiii List of Abbreviations ..................................................................................................... xv 1 Introduction and Literature Review ...................................................................... 1 1.1 Francisella tularensis ..................................................................................... 1 1.1.1 A Brief History of Tularemia ........................................................... 1 1.1.2 F. tularensis as a Biological Weapon ............................................... 3 1.1.3 F. tularensis Species, Subspecies, and Genetics ............................... 4 1.1.4 Vectors, Transmission, and Clinical Disease .................................... 7 1.1.5 F. tularensis Invasion of and Survival in Host Cells ......................... 9 1.1.6 F. tularensis Pathogenesis .............................................................. 11 1.1.7 Immune Responses to F. tularensis ............................................... 12 1.1.7.1 Innate Immunity ............................................................. 12 1.1.7.2 Adaptive Immunity ......................................................... 14 vii 1.2 Virulence Factors of F. tularensis ................................................................. 17 1.2.1 Francisella Pathogenicity Island .................................................... 17 1.2.2 Additional Francisella Secretion Systems ...................................... 19 1.2.3 F. tularensis Capsule ..................................................................... 20 1.2.4 F. tularensis LPS ........................................................................... 21 1.2.5 F. tularensis Envelope Proteins ...................................................... 22 1.2.5.1 Outer Membrane Proteins ............................................... 22 1.2.5.2 Periplasmic Proteins ....................................................... 24 1.2.5.3 Inner Membrane Proteins ................................................ 25 1.2.6 Disulfide Bond Formation Protein A and Substrates ...................... 27 1.3 F. tularensis Vaccines .................................................................................. 28 1.3.1 History of Tularemia Vaccines ....................................................... 28 1.3.2 Animal Models .............................................................................. 30 1.3.3 Immune Correlates of Protection .................................................... 32 1.3.4 Subunit, Killed Whole-Cell, or Live-Attenuated? ........................... 34 1.3.5 Live-Attenuated Vaccines Derived from LVS vs. SchuS4 .............. 36 1.4 Gram-Negative Bacterial Peptidoglycan ....................................................... 38 1.4.1 Peptidoglycan General Structure .................................................... 38 1.4.2 Peptidoglycan Synthesis ................................................................ 39 1.4.3 Peptidoglycan Recycling ................................................................ 40 1.5 Goals and Significance of my Dissertation Studies ....................................... 41 2 A Periplasmic L,D-Carboxypeptidase is Important for Cell Shape, Membrane Integrity, and Virulence in F. tularensis ............................................................ 44 viii 2.1 Abstract ................................................................................................... 45 2.2 Introduction .................................................................................................. 46 2.3 Results ..................................................................................................
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