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Iron Deficiency Anemia and the Pathogenesis of Falciparum Malaria

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Iron Deficiency Anemia and the Pathogenesis of Falciparum Malaria IRON DEFICIENCY ANEMIA AND THE PATHOGENESIS OF FALCIPARUM MALARIA Morgan McFarland Goheen A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology in the School of Medicine. Chapel Hill 2016 Approved by: Carla Cerami Myron S. Cohen Kristina De Paris Raj S. Kasthuri Thomas H. Kawula Steven R. Meshnick © 2016 Morgan McFarland Goheen ALL RIGHTS RESERVED ii ABSTRACT Morgan McFarland Goheen: Iron Deficiency Anemia and the Pathogenesis of Falciparum Malaria (Under the direction of: Carla Cerami and Steven R. Meshnick) Anemia, primarily iron deficiency anemia (IDA), affects up to 50% of pregnant women and 40% of preschool children in the developing world, significantly impacting perinatal and developmental health. However, clinical studies have found (1) iron deficiency protects from malaria, and (2) administration of iron to iron deficient individuals may increase the risk of malaria, thus complicating universal iron supplementation recommendations in malaria-endemic areas. Our lab developed an in vitro model, obtaining red blood cells (RBCs) from IDA or healthy donors at UNC, to study mechanisms of malaria-associated IDA protection and iron treatment risk. We demonstrated decreased P.falciparum invasion and growth in IDA RBCs and increased infection susceptibility in young RBCs and reticulocytes. Given iron is essential for the parasite, it was previously thought iron deficiency inhibited malaria through starvation. However, IDA also limits erythropoiesis and induces physiologic RBC changes. Our UNC-based studies thus generated a novel and paradigm-shifting hypothesis – namely that changes in RBC properties and the RBC population structure drive IDA resistance to and iron supplementation risk for malaria. Our next objective was to evaluate this hypothesis in pregnant women and children from a malaria-endemic area, via comprehensive longitudinal examination of P.falciparum pathogenesis in RBCs drawn from iron deficient Gambian children and pregnant women before, during, and after iron supplementation. RBCs were collected from 135 children and 165 pregnant women throughout 12 weeks of iron supplementation and used in flow cytometry-based in vitro assays. Our results demonstrate P.falciparum erythrocytic stage growth in vitro is low at baseline, correlating with hemoglobin levels and mean corpuscular volume. We also determined parasite growth increases during supplementation, using RBCs from both children and pregnant women. Additionally, we found reduced parasite invasion in RBCs from iron deficient Gambian children, which increases during iron supplementation. The elevated growth iii rates following iron supplementation paralleled increases in circulating reticulocytes and other markers of young RBCs, kinetics of which correlate with overall increased erythropoiesis. We conclude malaria growth in vitro corresponds with elevated erythropoiesis, an inevitable consequence of iron supplementation. Our findings imply iron supplementation in malarious regions should be accompanied by effective preventative measures against falciparum malaria. iv ACKNOWLEDGEMENTS It is difficult to describe the amount of gratitude I feel towards so many people in my life and to adequately thank everyone for helping me reach this point. I would like to start off by thanking my family and friends for their never-ending love and support, without which I would not ever have reached the point where I am today. I fully recognize just how fortunate I am to have such an incredible support system that has been with me for so many years. Knowing I always have my family believing in me has made all the difference when it comes to believing in myself and aiming for the next goal, and it is my family who has also demonstrated to me the importance of hard work and striving to be a good citizen. I am always inspired by them. I am similarly constantly amazed when I look back at the wonderful friendships I have been so fortunate to develop during each stage of my life, the core of which began in pre-school and have remained strong to this day. I would also like to thank my newfound Gambian friends, who have offered me a completely fresh perspective on life and supported me in countless ways regarding my research efforts as well as welcoming me into a new culture; I can truly say I feel like I have found a home away from home with them. It also goes without saying that I owe the ability to have done much of the work in this dissertation to the dedication and hard work of countless MRC staff, not to mention the people who were willing to participate in our research. I would certainly be remiss without mentioning my lab colleagues who have been incredibly rewarding to work with over the past several years, as well as the amazing support constantly available from the MD/PhD program leadership. Nor do I want to forget to thank all of institutions which contributed to the research funding, fellowship awards, and travel grants which I am so lucky to have benefited from, as well as my dissertation committee. Finally, I wish to sincerely thank my research mentors for the amazing opportunities they have provided me and the vast amounts of effort they have put in towards helping me develop as a scientist. I feel I could never come close to repaying them, but I will do my best to continue contributing to science in a meaningful way as an attempt to honor their dedication. v PREFACE The material included in Chapter 2 is a replication of our paper published in Nature Communications (2014) and is included here with permission from Nature Publishing Group. The authors of this paper are, in order: Clark MA, Goheen MM, Fulford A, Prentice AM, Elnagheeb MA, Patel J, Fisher N, Taylor SM, Kasthuri RS, Cerami C. As second author on this paper, I was involved in much of the experimental work in terms of data collection and analysis, as well as discussion of interpretations and ideas and editing of the manuscript. As first author, Martha Clark was unquestionably the one who spearheaded the research and development of this paper. The material included in Chapter 3 is a replication of our paper published in the British Journal of Haematology (2016) and is included here with permission from John Wiley and Sons. The authors of this paper are, in order: Goheen MM, Clark MA, Kasthuri RS, Cerami C. As first author on this paper, I was centrally involved in experimental design, data analysis and results interpretation, and writing of the manuscript. The material included in Chapter 4 is a replication of a manuscript conditionally accepted to EBioMedicine following minor formatting revisions. The authors of this paper are, in order: Goheen MM, Wegmuller R, Bah A, Darboe B, Danso E, Affara M, Gardner D, Patel JC, Prentice AM, Cerami C. As first author on this paper, I was centrally involved in experimental design, data analysis and results interpretation, and writing of the manuscript. I have also worked extensively with Dr. Meshnick and his epidemiology Ph.D. student Jordan Cates to include additional analyses and discussion of analytical approaches beyond the scope of our accepted manuscript at the end of this chapter. The material included in Chapter 5 is a draft of a manuscript we plan to submit in the near future. The anticipated authorship of this paper would be, in order: Goheen MM, Bah A, Wegmuller R, Darboe B, Danso E, Patel JC, Prentice AM, Cerami C. As fist author on this planned manuscript, I have been centrally involved in experimental design, data analysis and results interpretation, and writing of the manuscript. vi TABLE OF CONTENTS CHAPTER ONE: INTRODUCTION TO ERYTHROCYTE ALTERATIONS WHICH IMPACT FALCIPARUM MALARIA INFECTION…………………………………………………………………….…….…1 1.1 INTRODUCTION ................................................................................................................................. 1 1.2 HEMOGLOBINOPATHIES.................................................................................................................. 4 1.2.1 Sickle-cell Trait ............................................................................................................................. 4 1.2.2 Hemoglobin C .............................................................................................................................. 6 1.2.3 Hemoglobin E ............................................................................................................................... 7 1.2.4 Thalassemias ............................................................................................................................... 8 1.3 ENZYMATIC DEFICIENCIES ........................................................................................................... 11 1.3.1 Glucose-6-Phosphate Dehydrogenase Deficiency .................................................................... 11 1.3.2 Pyruvate Kinase Deficiency ....................................................................................................... 14 1.4 RBC MORPHOLOGY AND THE CYTOSKELETON ........................................................................ 15 1.5 BLOOD GROUPS ............................................................................................................................. 18 1.5.1 ABO Blood Groups ..................................................................................................................... 18 1.5.2
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