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The Mechanism of Human Apolipoprotein L1 Killing of African

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The Mechanism of Human Apolipoprotein L1 Killing of African THE MECHANISM OF HUMAN APOLIPOPROTEIN L1 KILLING OF AFRICAN TRYPANOSOMES by AMY STYER GREENE (Under the Direction of STEPHEN HAJDUK) ABSTRACT Trypanosoma brucei brucei parasites are rapidly lysed by human serum due to innate immune factors called trypanosome lytic factors (TLFs). Related parasites T. b. rhodesiense and T. b. gambiense evolved resistance to the TLFs and cause the deadly disease human African trypanosomiasis. My work focused on TLF-1, a high density lipoprotein particle (HDL) containing the pore-forming toxin Apolipoprotein L1 (ApoL1) and hemoglobin-binding protein haptoglobin related protein (Hpr). I found that TLF-1 and ApoL1 cause rapid changes at the plasma membrane, including dissipating the plasma membrane potential and inducing sensitivity to hypotonic lysis. ApoL1-induced osmotic stress at the plasma membrane leads to water influx and eventual lysis. Moreover, osmotic lysis is exacerbated by oxidizing agents and molecules which bind to free thiols in proteins. My work suggests that ApoL1 in TLF-1 traffics to the plasma membrane of T. b. brucei, facilitating sodium influx, ionic imbalance, oxidation of osmoregulatory proteins, cell swelling, and trypanosome lysis. INDEX WORDS: Trypanosome, Trypanosoma brucei, ApoL1, HDL, cell death, oxidative stress, osmotic stress, plasma membrane potential THE MECHANISM OF HUMAN APOL1 KILLING OF AFRICAN TRYPANOSOMES by AMY STYER GREENE B.S., University of Delaware, 2010 A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2016 © 2016 Amy Styer Greene All Rights Reserved THE MECHANISM OF HUMAN APOLIPOPROTEIN L1 KILLING OF AFRICAN TRYPANOSOMES by AMY STYER GREENE Major Professor: Stephen Hajduk Committee: Robert Sabatini Kojo Mensa-Wilmot Zachary Wood Amy Medlock Electronic Version Approved: Suzanne Barbour Dean of the Graduate School The University of Georgia May 2016 DEDICATION I dedicate this thesis to those I have known and lost during my six years at UGA: Howard Styer “Poppop”, Aunt Miriam Ruth, Dr. Laura Cliffe, Dr. Tariq Perwez, Father Tom Vigiolatta, Dr. Oliver Ludwig, Snizhana Radzetska, Kortney Gordon and her pre- born baby Sophie, Jon Scarfenberger, Dr. Paul Grutsch, and Dr. Martin Kleiber. iv ACKNOWLEDGEMENTS Thanks to everyone! All praise to the Eucharistic Jesus who comes down to earth to be with my sinful, stressed-out self. I especially thank my husband Fadi Greene who put off his career to come down to GA and support me as I finished my Ph.D. a semester later than originally planned. I’m also very thankful for the many hours Fadi saved me by helping to format and edit this dissertation. Numerous friends, family, and lab co-workers have encouraged me and given me great ideas during this work. My committee is made up of a diverse group of professors who have contributed to my development in different ways. Steve Hajduk is a great scientist to have as a Ph.D. mentor. He is always creative and willing to support my ideas and models. He generously sent me to the biology of parasitism course and several conferences which were highlights of my time here. I am also thankful to have a boss who is supportive of my pursuit of a teaching-oriented career. Bob Sabatini always asks questions to ensure that I can articulate ideas well. Zac Wood thinks about things in terms of structure and kinetics, and he brings a joyful optimism about science to committee meetings. Kojo thinks outside the box, and asks questions that make me think. His perspectives on curing African trypanosomiasis as a disease is also helpful. Amy Medlock’s expertise was helpful in my introductory work on reconstituting globins with heme, and I am thankful that she always takes the time to ask about me as a person as well as about my science. v There are other professors at UGA who deserve recognition. I must thank CTEGD professor Dr. Roberto Docampo and Dr. Silvia Moreno for helpful discussions about the plasma membrane potential and osmotic stress in trypanosomes. Dr. Paula Lemons has been a wonderful mentor and resource for my interest in teaching and learning. I have spent many hours with her working together on teaching projects and discussing career plans. Dr. Paula Lemons and Dr. John Rose have also been extremely helpful in writing dozens of letters of recommendation for teaching positions I have applied for. Thanks to Dr. Jon Rose and Dr. Allan Pryzbyla for allowing me to give guest lectures in their biochemistry classes. It has also been a joy to work with Dr. Kris Miller who co-ordinates biology lab instructors. She gives me the freedom to teach and assess my students in creative ways, making my time in the biology 1108 lab a highlight of my Ph.D. I have had the joy of working with two talented undergraduates in the lab: Allen Witt and Savanah-Rose Pena. Both worked on the biogenesis of TLF-2 project, which I have unfortunately not been able to pull into a publication-style chapter for this dissertation. They are now both in medical school, and I hope that the experience they had performing experiments, reading articles, and writing about their results helped them to become better doctors and collaborators with scientists. vi TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ............................................................................................... v LIST OF TABLES ............................................................................................................ ix LIST OF FIGURES .......................................................................................................... x CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW .............................................. 1 Introduction to Trypanosomes 1 Trypanosome Lytic Factors (TLFs) ............................................................ 5 Mechanisms of Trypanosome Lysis by TLF-1 ......................................... 15 Mechanisms of TLF Resistance ............................................................... 27 Biology Behind TLF Uptake ..................................................................... 32 Cell Death Pathways in Trypanosomes ................................................... 38 Oxidative Stress and the Lysosomal Model for TLF Lysis ....................... 48 Osmotic Stress and the Plasma Membrane Model for TLF Lysis ............ 55 TLF and ApoL1 in Human Biology ........................................................... 63 Conclusion ............................................................................................... 76 2 TRYPANOSOME LYTIC FACTOR INITIATES OXIDATION-STIMULATED OSMOTIC LYSIS OF TRYPANOSOMA BRUCEI BRUCEI ........................... 78 Abstract .................................................................................................... 79 Introduction .............................................................................................. 79 Results ..................................................................................................... 82 vii Discussion ............................................................................................... 99 Experimental Procedures ....................................................................... 105 3 APOL1 INDUCES A LOSS OF PLASMA MEMBRANE POTENTIAL LEADING TO OSMOTIC LYSIS OF TRYPANOSOMA BRUCEI BRUCEI ................... 112 Abstract .................................................................................................. 113 Introduction ............................................................................................ 113 Results ................................................................................................... 116 Discussion ............................................................................................. 128 Experimental Procedures ....................................................................... 133 Supplementary data ............................................................................... 136 4 APOL1 TOXICITY TO HUMANS AND TRYPANOSOMES…………………145 Abstract .................................................................................................. 146 Review Article ........................................................................................ 146 5 MODEL FOR TLF LYSIS OF TRYPANOSOMA BRUCEI BRUCEI ............. 156 ALL REFERENCES .................................................................................................... 161 viii LIST OF TABLES Page Table 1.1: Redox Regulatory Enzymes in T. brucei ...................................................... 53 Table 1.2: Concentration of Osmolytes in T. brucei Cytosol and Human Serum ........... 56 Table 1.3: Plasma Membrane Channels in T. brucei .................................................... 59 Supplemental Table 3.1: Timeline for TLF-1 Induced Lysis of T. b. brucei.................. 143 ix LIST OF FIGURES Page Figure 1.1: ApoL1 Primary Structure ............................................................................... 8 Figure 1.2: Hpr alone does not kill T. b. brucei .............................................................. 11 Figure 1.3: Sequence Alignment of Human Haptoglobin (Hp1) and Hpr ....................... 12 Figure 1.4: Comparison between TLF-1 and TLF-2 ...................................................... 14 Figure 1.5: Three Organelles for TLF Activity ................................................................ 16 Figure 1.6: Schematic for Hb-initiated Lipid Peroxidation .............................................
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