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1 the Importance of Listeriolysin O in Host Cell Invasion by Listeria The Importance of Listeriolysin O in Host Cell Invasion by Listeria monocytogenes and its Use in Vaccine Development Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Christopher Phelps Graduate Program in Microbiology The Ohio State University 2019 Dissertation Committee Stephanie Seveau, Advisor Prosper Boyaka John Gunn Chad Rappleye 1 Copyrighted by Christopher Phelps 2019 2 Abstract Listeria monocytogenes is a facultative intracellular pathogen and the etiological agent of the life-threatening disease listeriosis. L. monocytogenes is ubiquitous in the environment and frequently contaminates food products, including beef, poultry, vegetables, dairy products, and particularly ready-to-eat foods. Because L. monocytogenes can grow under conditions that are typically used for food preservation, including low temperatures and high salt concentrations, preventing contamination and effectively sanitizing food production equipment is both costly and difficult. Consumption of contaminated food by otherwise healthy adults usually results in minor cases of noninvasive listeriosis that do not require treatment. However, particularly susceptible populations including pregnant women, the elderly, and those with compromised immune systems can develop severe invasive listeriosis in which the bacteria can cross the intestinal barrier to infect the liver, spleen, and ultimately the central nervous system, as well as the placenta, in the case of pregnant women. L. monocytogenes has the ability to invade and replicate within a wide variety of phagocytic and nonphagocytic cells. L. monocytogenes has been known to use two major invasion factors to enter nonphagocytic cells, InlA and InlB. After endocytosis of the bacterium, L. monocytogenes disrupts the vacuole and enters the host cell cytosol using ii the pore-forming toxin, listeriolysin O (LLO). In the cytosol, the bacterium replicates and spreads to adjacent cells. Though InlA and InlB have been considered the primary invasion factors, LLO was recently identified as an additional factor in the invasion of hepatocytes. Importantly, during infection, all three of these factors are co-expressed and have the potential to act in concert with one another. In our work, for the first time, we demonstrate the relative roles and importance of LLO, InlA, and InlB during host cell invasion. LLO is an important invasin in a variety of hepatocytes, but not placental cells, or endothelial cells, and cooperates with InlA to potentiate invasion. In addition to promoting invasion of enterocytes, InlA also promotes association with human hepatocytes and placental cells. We identified no role for InlB initially. We only observed a role for this factor when we introduced a constitutively active transcription regulator PrfA*, suggesting that InlB may not be as critical to host cell invasion in strains with properly regulated virulence regulon expression. In light of the importance of LLO during infection, we have developed a vaccine that uses an LLO toxoid variant (LLOT) as an antigen and cholera toxin as an adjuvant. We found that this vaccine leads to anti-LLO antibody production and the development of a Th1 type immune response. Protection in the intravenous, non-pregnant murine model appears to be independent of anti-LLO antibodies in the context of full functional T cell response. iii Dedication I would like to dedicate this document to my family and friends for their never-ending support throughout my education. I would, in particular, like to thank my wife, Emily Phelps, for her love, support, and encouragement and for never failing to believe in me. iv Acknowledgments I would like to thank members of the Seveau lab that have been supportive both in our research and in my development throughout my time as a Ph.D. student: Dr. Jonathan Lam, Lauren Johnson, Siavash Azari, Dr. Sarika Pathak-Sharma, Dr. Joanna Marshall, Jasneet Singh, Elizabeth Puleo, Bella Cho, and Meghan Linz. I would like to acknowledge and thank our collaborators at Ohio State who have made many important contributions to this work. I would like to thank Dr. Prosper Boyaka and his lab members Zayed Attia and Haley Steiner for their assistance in both the development and implementation of our vaccine project. Dr. Abhay Satoskar and his lab member Sanjay Varikuti also provided a great deal of assistance with mouse infections and the development of the vaccine project. Dr. Mikhail Gavrilin provided significant assistance and advice in developing new quantitative PCR protocols for our projects. Dr. Xiaoli Zhang and Yubo Tan provided assistance with statistical analysis of our data. I would like to acknowledge our funding source, the National Institute of Health, NIAID. I would also like to acknowledge my committee members, Dr. Prosper Boyaka, Dr. John Gunn, and Dr. Chad Rappleye, for their comments and suggestions during committee meetings and their willingness to be references both for various grant applications and my job search. Last and most importantly, I would like to thank my v advisor, Dr. Stephanie Seveau for her support, dedication, and patience as she has guided me through my doctoral training. vi Vita 2010-2013……………………………………………...Undergraduate Research Assistant Department of Biological Sciences Bowling Green State University 2013……………………………………………………………………..B.S. Microbiology Magna Cum Laude Bowling Green State University 2013-2015…………………………………………………...Graduate Teaching Associate Department of Microbiology The Ohio State University 2015-2018…………………………………………………...Graduate Research Associate Department of Microbiology The Ohio State University 2017-2019…………………………………………Delegate (Representing Microbiology) Council of Graduate Students The Ohio State University 2019-present…………………………………………………Graduate Teaching Associate Department of Microbiology The Ohio State University vii Publications Phelps, C.C., Vadia, S., Arnett, E., Tan, Y., Zhang, X., Pathak-Sharma, S., Gavrilin, M.A., Seveau, S. (2018) Relative Roles of Listeriolysin O, InlA, and InlB in Listeria monocytogenes Uptake by Host Cells. Infect Immun 86(10):e00555-18. https://doi.org/10.1128/IAI.00555-18. PMID: 30061379 Phelps, C.C., Vadia, S., Boyaka, P.N., Varikuti, S., Attia, Z., Dubey, P., Satoskar, A.R., Seveau, S. A Listeriolysin O_Toxoid-Based Vaccine Protects Mice against Listeria monocytogenes. (Manuscript in Preparation) Fields of Study Major Field: Microbiology viii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments............................................................................................................... v Vita .................................................................................................................................... vii List of Tables ..................................................................................................................... xi List of Figures ................................................................................................................... xii Chapter 1. Introduction ....................................................................................................... 1 Listeria monocytogenes .................................................................................................. 1 1.1.1 Listeriosis ...................................................................................................... 1 1.1.2 Intracellular lifecycle of L. monocytogenes .................................................. 4 1.1.3 L. monocytogenes virulence factors ............................................................. 6 1.1.4 PrfA, the regulator of virulence .................................................................... 7 1.1.5 InlA ............................................................................................................. 11 1.1.6 InlB ............................................................................................................. 13 1.1.7 Listeriolysin O ............................................................................................ 15 L. monocytogenes infection in vivo.............................................................................. 21 1.1.8 Innate Immune Responses .......................................................................... 21 1.1.9 Adaptive Immune Responses ...................................................................... 24 Research and specific aims ........................................................................................... 26 Chapter 2. Roles for Listeriolysin O, InlA, and InlB in Listeria monocytogenes Uptake by Host Cells ..................................................................................................................... 28 2.1 Introduction ............................................................................................................. 28 2.2 Materials and Methods ............................................................................................ 31 2.3 Results ..................................................................................................................... 43 2.4 Discussion ..............................................................................................................
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