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<I>Plasmodium Falciparum&L University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 10-19-2010 Phenotypic and Genotypic Analysis of In Vitro Selected Artemisinin Resistant Plasmodium falciparum Matthew cottS uckT er University of South Florida Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the American Studies Commons, Public Health Commons, and the Public Policy Commons Scholar Commons Citation Tucker, Matthew Scott, "Phenotypic and Genotypic Analysis of In Vitro Selected Artemisinin Resistant Plasmodium falciparum" (2010). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/3495 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Phenotypic and Genotypic Analysis of In Vitro Selected Artemisinin Resistant Plasmodium falciparum by Matthew Scott Tucker A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Global Health College of Public Health University of South Florida Major Professor: Dennis E. Kyle, Ph.D. Azliyati Azizan, Ph.D. Jacqueline Cattani, Ph.D. John Dame, Ph.D. Boo Kwa, Ph.D. Date of Approval: October 19, 2010 Keywords: Malaria, Drug, Resistance, Molecular, Mechanism Copyright © 2010, Matthew Scott Tucker Acknowledgments This study represents a substantial amount of work that could not have been completed without the help of many people. I thank my advisor, Dr. Dennis Kyle, for helping me polish skills that will help me become an excellent research scientist in the future. Dr. Kyle has been a great source of knowledge and advice during my time in his laboratory. He is also a wonderful teacher and person who has helped me not only succeed in the laboratory, but he has helped me with various administrative issues while at USF. I consider myself lucky to have found him as a research mentor. I would also thank my other committee members: Dr. Azliyati Azizan, Dr. Jacqueline Cattani, Dr. John Dame, and Dr. Boo Kwa for adding expertise to my dissertation research and taking the time to peruse my thesis in a time period that is relatively short considering the length of the document. My mother and brother have been a constant source of support during my academic career. My mother has instilled in me an excellent work ethic and determination, and she has always encouraged me to succeed at every endeavor. My father has helped me succeed as a student, by showing me the importance of knowledge and education. I wish to thank my wife Kim, for her constant support while I have been in graduate school. She has helped me become a better person and I thank her dearly for putting up with me during the grind of my graduate career. Finally, I would like to recognize my co-workers Alexis LaCrue, Tina Mutka, Kansas Sparks, and Janus Patel for assisting me in different experiments that contributed to my research. Table of Contents List of Tables ..................................................................................................................... vi List of Figures .................................................................................................................. viii Abstract .............................................................................................................................. xi Chapter One: Introduction ...................................................................................................1 Malaria: Background ...............................................................................................1 Plasmodium spp. Life Cycle ....................................................................................5 Mosquito (Definitive Host) ..........................................................................5 Human (Intermediate Host) .........................................................................6 Malaria: Life Cycle in Relation to Cell Cycle ...........................................10 Malaria: Clinical Manifestations and Diagnosis ....................................................12 Uncomplicated Malaria ..............................................................................12 Severe Malaria ...........................................................................................13 Global Impact of Malaria .......................................................................................15 Malaria Public Health Control and Eradication Efforts .........................................18 Malaria in the United States .......................................................................20 Current Malaria Control Programs ........................................................................21 Vaccines .................................................................................................................27 Pre-erythrocytic Stage ................................................................................27 Erythrocytic Stage ......................................................................................30 Transmission Blocking Vaccines ...............................................................32 Antimalarial Drugs for Treatment .........................................................................35 Quinolines ..................................................................................................36 Quinine ...........................................................................................37 Chloroquine....................................................................................38 Mefloquine, Other Aminoalcohols, and Primaquine .....................39 Amodiaquine and Piperaquine .......................................................41 Antifolates ..................................................................................................42 Atovaquone ................................................................................................43 Antibiotics ..................................................................................................44 Artemisinins ...............................................................................................45 Antimalarial Drug Recommendations ...................................................................50 Prophylaxis ................................................................................................50 Curative Treatment ....................................................................................50 i Antimalarial Drug Resistance ................................................................................52 In Vivo Measures of Drug Resistance ........................................................54 Quinolines .......................................................................................................... 56 Chloroquine....................................................................................56 Amodiaquine and Piperaquine .......................................................62 Arylaminoalcohols .....................................................................................63 Quinine ...........................................................................................63 Mefloquine and Other Arylaminoalcohols ....................................64 Antifolates ..................................................................................................69 Atovaquone ................................................................................................71 Artemisinins ...............................................................................................72 Preliminary Studies from the Kyle Laboratory ......................................................80 Dormancy ...................................................................................................80 Studies Relevant to This Work ..................................................................91 Molecular Characterization of Artemisinin Resistance .............................93 Dormancy, Recrudescence, and Artemisinin Resistance ...........................97 Focus of Study .......................................................................................................98 Chapter Two: Induction of High Level Artemisinin Resistance and Phenotypic Characterization (Specific Aim 1) .............................................................................112 Rationale for Study ..............................................................................................112 Materials and Methods .........................................................................................115 Parasites and In Vitro Culture ..................................................................115 Development of Resistant Parasite Lines In Vitro ...................................115 Quantitative Recrudescence Assays ........................................................117 W2 Recovery Assay .....................................................................117 Initial D6 Recovery Assay ...........................................................118 Adapting D6 Parasites Beyond Clinically Relevant Concentrations .......................................................................119 Growth Assay...........................................................................................120 In vitro Drug Susceptibility
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