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The Role of Rhomboid Proteases and a Oocyst Capsule Protein

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The Role of Rhomboid Proteases and a Oocyst Capsule Protein THE ROLE OF RHOMBOID PROTEASES AND A OOCYST CAPSULE PROTEIN IN MALARIA PATHOGENESIS AND PARASITE DEVELOPMENT BY PRAKASH SRINIVASAN Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Advisor: Prof. Marcelo Jacobs-Lorena Department of Genetics CASE WESTERN RESERVE UNIVERSITY August, 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS Table of Contents 1 List of Tables 2 List of Figures 4 Acknowledgements 5 Abstract 7 CHAPTER 1: Introduction and Research Objectives 9 Introduction 10 Malaria: History and Facts 10 Discovery of Mosquitoes as vectors 10 Malaria: Life Cycle 12 Life cycle in the vertebrate host 12 Life cycle in the mosquito 15 Sporozoite invasion of the liver 29 Study of gene function in parasites 32 Research Objectives 34 CHAPTER 2: Analysis of Plasmodium and Anopheles Transcriptomes during Oocyst Differentiation 37 CHAPTER 3: PbCap380, a novel Plasmodium Oocyst Capsule Protein is Essential for Parasite Survival in the Mosquito 61 CHAPTER 4: Distinct Roles for Rhomboid1 and Rhomboid3 Proteins in Malaria Pathogenesis and Plasmodium Development 82 CHAPTER 5: Conclusions and Future Directions 107 1 Conclusion 108 Future Directions 111 Bibliography 118 2 LIST OF TABLES CHAPTER 2 Table 2.1 48 CHAPTER 3 Table 3.1 77 CHAPTER 4 Table 4.1 94 3 LIST OF FIGURES CHAPTER 1 Figure 1.1 14 Figure 1.2 18 Figure 1.3 26 CHAPTER 2 Figure 2.1 47 Figure 2.2 49 Figure 2.3 51 Figure 2.4 53 Figure 2.5 56 Figure 2.6 57 CHAPTER 3 Figure 3.1 71 Figure 3.2 73 Figure 3.3 74 Figure 3.4 75 Figure 3.5 78 4 CHAPTER 4 Figure 4.1 91 Figure 4.2 93 Figure 4.3 95 Figure 4.4 97 Figure 4.5 98 Figure 4.6 99 Figure 4.7 100 Figure 4.8 101 Figure 4.9 102 5 Acknowledgements I have had the pleasure and privilege of working with a number of people during the course of my study. I would like to first thank my mentor, Dr. Marcelo Jacobs- Lorena for his support and guidance through all these years. His passion for science and an eagerness to face new challenges have always been motivating. His willingness to let me pursue my work independently has helped me develop my scientific knowledge and has given me the confidence to follow my scientific dreams. My sincere thanks to my committee members, Dr. Bruce Lamb, Dr. Peter Harte, Dr. Pete Zimmerman and Dr. Edward Stavnezer for their constructive criticisms and invaluable suggestions. I also thank the members of the MJL lab, past and present, for their support and for making the lab meetings a fun time (for the most part!). I would like to thank Anil Ghosh and Abraham Eappen for their help, particularly during my initial days in the lab. I take this opportunity to thank all my teachers for their encouragement and support, especially Dr. Patrick Gomez and Dr. Yogesh Shouche. I thank my friends Sumi, Sujit, Anirudh, Cristina and Jessica for their support and the fun memories. Special thanks to my dear friend Minnie for always being there, for the 6 stimulating discussions, the delicious meals (and the ‘one of a kind’ tea!) and wonderful memories. I would not be here if not for the unfathomable love and incredible support from my parents Srinivasan and Vimala. They have always believed in me and encouraged me to follow my dreams. The love and affection of my wonderful sister has been a source of energy. I thank them from the bottom of my heart. I’m forever indebted to my late grand parents, whose love, support and confidence in me have made me and still make me a better person in life. Finally, thanks to my dearest friend and my best half, Susham, with whom I have shared the best and worst times of my graduate life. I can definitely say without a doubt that she made graduate school a lot easier with her patience, support and love and has helped broaden my scientific thinking and believe in my abilities. 7 The Role of Rhomboid Proteases and a Oocyst Capsule protein in Malaria Pathogenesis and Parasite Development Abstract by PRAKASH SRINIVASAN Plasmodium, the etiological agent of malaria causes more than a million deaths mostly in children under the age of five, and nearly 500 million people suffer from this disease every year. The lack of an effective vaccine and the spread of resistance against currently used drugs underscores the need to identify new targets and approaches to control this disease. Plasmodium life cycle takes place in two hosts, namely, the vertebrate and the mosquito. The sexual stages of the parasite occur in the mosquito. This absolute dependence on the mosquito for parasite represents a potential weak link that could be exploited. A better understanding of parasite development in the mosquito may identify new targets for intervention. In this work, I have attempted to address some of the questions pertaining to specific developmental events that take place during parasite development in the midgut. Soon after fertilization the motile ookinete that is formed inside the blood meal transforms 8 into a sessile oocyst. The parasite then enlarges in size and a single oocyst can produce thousands of sporozoites, the infective forms. The factors that regulate oocyst differentiation are not well understood. This study identifies several novel genes that are expressed during oocyst development. During parasite development in the mosquito, a drastic reduction in number occurs as the parasite transforms from one stage to the other. However, once oocysts are formed they appear to be resistant against the mosquito defenses. In this study we identify an important function for a oocyst capsule protein in parasite survival in the mosquito. Finally, this work also sheds light on the role of two rhomboid family serine proteases in parasite development and malaria pathogenesis. Overall, this study advances our understanding of Plasmodium development in the mosquito as well as in the vertebrate host and identifies potential targets for interfering with parasite transmission and malaria pathogenesis. 9 CHAPTER 1 Introduction and Research Objectives 10 Introduction Malaria: History and Facts Malaria is one of the oldest and the most debilitating diseases known to man. Nearly 50% of the world’s population is at risk and an estimated 1 to 2.7 million people die of malaria every year, mostly children under the age of five (Breman et al. 2001, Greenwood and Mutabingwa 2002). Malaria is thought to have been prevalent as early as 2700 B.C. Two of the most widely used drugs of recent times, artemisinin and quinine were in fact derived from plants used in ancient Chinese and South American medicine to treat malaria-like symptoms. However the causative agent, Plasmodium, a protozoan parasite was discovered only a century ago. Charles Lavern in 1880 was the first to identify parasites in the blood of a patient with symptoms of malaria. Since then four species of Plasmodium: P. falciparum, P. vivax, P. ovale and P. malariae that infect humans have been identified. Malaria: Discovery of mosquitoes as vectors A major breakthrough in the control of malaria came when Ronald Ross (1897) discovered mosquitoes as vectors for malaria transmission. Ross was very well aware of the importance of this discovery and this is reflected in his poem, This day designing God Hath put into my hand 11 A wondrous thing; and God Be praised. At his command I have found thy cunning seeds Oh million-murdering Death, I know that this little thing A million men will save Oh death where is thy sting? Thy victory oh grave? Subsequently, female Anopheles mosquitoes were identified as the sole vectors of human malaria transmission. This absolute dependence on the mosquitoes for parasite transmission reveals a potential weak link that has been exploited by the use of insecticides (mainly DTT and pyrithroids) to reduce malaria. The use of drugs against the parasite and insecticides against mosquito resulted in a drastic reduction of malaria. However, emergence of insecticide resistant mosquitoes (Hemingway et al. 2004) and multiple drug resistant parasites (Sidhu et al. 2002, Price et al. 2004, Valderramos and Fidock 2006) has led to a global crisis in controlling this disease. More information on the milestones and history of malaria are recounted by Harrison (1978) and Desowitz (1991). The following web sites also provide useful information on malaria. http://www.malariasite.com/malaria/History.htm http://www.cdc.gov/malaria/history/index.htm 12 Malaria: Life cycle The life cycle of the malaria parasite involves development in two different hosts: vertebrate host (exoerythrocytic and erythrocytic forms (also called asexual or blood stage)) and mosquito vector (sexual stage) (Fig.1.1 and Fig.1.2). Life cycle in the vertebrate host Infection begins soon after the transfer of sporozoites (infective forms) into a naïve host by an infected mosquito (Fig.1.1). The sporozoite carried through the blood circulation infects the liver (exoerythrocytic stage). After 4-6 days, a single infected hepatocyte can produce nearly 30,000 merozoites Upon rupture of the infected hepatocyte, merozoites released into the blood stream invade the red blood cells (RBCs) and start the erythrocytic stage of development. P. falciparum is the most widespread and the deadliest of the four human malaria species. A unique feature of P. vivax, P. ovale and P.cynomolgi (monkey malaria) is the relapse of malaria.
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