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GLYCAN TRIGGERS of LIFE CYCLE DEVELOPMENT in the APICOMPLEXAN PARASITE CRYPTOSPORIDIUM a Dissertation Submitted to the Graduate

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GLYCAN TRIGGERS of LIFE CYCLE DEVELOPMENT in the APICOMPLEXAN PARASITE CRYPTOSPORIDIUM a Dissertation Submitted to the Graduate GLYCAN TRIGGERS OF LIFE CYCLE DEVELOPMENT IN THE APICOMPLEXAN PARASITE CRYPTOSPORIDIUM A Dissertation Submitted to the Graduate Faculty of the North Dakota State University of Agriculture and Applied Science By Adam LeRoy Edwinson In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Major Program: Molecular Pathogenesis April 2017 Fargo, North Dakota North Dakota State University Graduate School Title GLYCAN TRIGGERS OF LIFE CYCLE DEVELOPMENT IN THE APICOMPLEXAN PARASITE CRYPTOSPORIDIUM By Adam LeRoy Edwinson The Supervisory Committee certifies that this disquisition complies with North Dakota State University’s regulations and meets the accepted standards for the degree of DOCTOR OF PHILOSOPHY SUPERVISORY COMMITTEE: Dr. John McEvoy Chair Dr. Teresa Bergholz Dr. Eugene Berry Dr. Glenn Dorsam Dr. Mark Clark Approved: 06/06/17 Dr. Peter Bergholz Date Department Chair ABSTRACT Cryptosporidium is an apicomplexan parasite that causes the diarrheal disease cryptosporidiosis, an infection that can become chronic and life threating in immunocompromised and malnourished individuals. Development of novel therapeutic interventions is critical as current treatments are entirely ineffective in treating cryptosporidiosis in populations at the greatest risk for disease. Repeated cycling of host cell invasion and replication by sporozoites results in the rapid amplification of parasite numbers and the pathology associated with the disease. Little is known regarding the factors that promote the switch from invasion to replication of Cryptosporidium, or the mechanisms underlying this change, but identification of replication triggers could provide potential targets for drugs designed to prevent cryptosporidiosis. The focus of this dissertation was to identify potential triggers and the mechanisms underlying the transition from invasive sporozoite to replicative trophozoites in Cryptosporidium. We demonstrate glycoproteins secreted by host cells promote the transition from invasion to replication in Cryptosporidium, and free Gal-GalNAc triggers nuclear division in linear and rounded sporozoites. The proportion of rounded and multinucleated cells in response to the host secretions differed between C. parvum and C. hominis, the two species of greatest concern to human health, with C. parvum sporozoites progressing towards rounding and replication faster. We demonstrated the use of glycomimetic polymers for studying Cryptosporidium biology. Slides imprinted with increasing densities of Gal and GalNAc had the greatest proportion of trophozoite development. Gal and GalNAc glycomimetic polymers were able to cause parasite replication; however the effect was less than what was observed in the presence of secreted host glycoproteins and free Gal-GalNAc. We also characterized a rhomboid protease (ROM) in Cryptosporidium which we name CpROM2, iii providing information regarding expression and localization of the protease during C. parvum development. Using inhibitors specific for ROM activity we show ROMs play a critical role in excystation, but are also required for the transition from invasion to replication in C. parvum. These findings have strengthened our understanding of how Cryptosporidium transitions from invasion to replication by identifying host glycoproteins and Gal-GalNAc as triggers for trophozoite development via a ROM driven mechanism. iv ACKNOWLEDGEMENTS This dissertation is a culmination of hard work, determination, encouragement and support from many different people. I would like to thank my advisor Dr. John McEvoy for taking a chance on me as an undergraduate student in the summer of 2011. I appreciate your guidance, friendship and willingness to give me an opportunity to grow as a scientist, but most importantly as a person. I also want to thank Dr. Teresa Bergholz, Dr. Eugene Berry, Dr. Mark Clark and Dr. Glenn Dorsam for serving on my committee and continued encouragement. I am also thankful to our collaborators Dr. Giovanni Widmer, Dr. Martin Kváč and Dr. Kamil Godula for providing insight and the resources to complete this work. A huge thank you needs to be given to Cathy Giddings for all of the support she has not only given me, but other students in the lab, department and campus. Without question I could not have gotten through the long days and weekends without her friendship. She made our lab feel like home, and that someone cared for us. Thank you to the McEvoy Lab grad students: Tu, Pumis, Ebot and Brianna for being great friends and always willing to share ideas, a laugh and lend a helping hand. Thanks to the amazing undergraduate students, Jennifer and Baustin for giving me the opportunity to mentor and share my passion for science with others. Thank you to the faculty and staff of the Microbiological Sciences Dept. and Graduate School for funding my research and allowing me the chance to pursue my degree. Thank you to the Department for giving me the opportunity to teach and for fostering a supportive environment, encouraging each student to reach their potential. I am grateful to all the faculty and staff for their support and friendship while guiding me as a student and researcher. I cannot thank my family and friends enough for their support, love and encouragement. To my parents, Dave, Tammy, Doug and Wendy and my siblings Jacob, Emily and Liz for always being a v presence, patient and understanding. To my Grandparents: Verne (Papa), Judy, Gayleen and Terry for your love, support, visits and always being just a phone call away. Lastly, thank you to my wife Jill for following me to Fargo and giving me the opportunity to pursue my dreams. You encourage my creativity, keep me grounded and make me a better person. Whether it be volunteering for Wish Fast, or running a marathon, you are and always have been by my side. Thank you for your warmth, love and support throughout this process and in life. vi TABLE OF CONTENTS ABSTRACT ................................................................................................................................... iii ACKNOWLEDGEMENTS ............................................................................................................ v LIST OF TABLES .......................................................................................................................... x LIST OF FIGURES ....................................................................................................................... xi LIST OF ABBREVIATIONS ...................................................................................................... xiii GENERAL INTRODUCTION AND RESEARCH OBJECTIVES............................................... 1 Introduction ................................................................................................................................. 1 Aims of the dissertation project .................................................................................................. 3 Organization of the dissertation .................................................................................................. 4 Overview of Cryptosporidium and cryptosporidiosis ................................................................. 4 Epidemiology of Cryptosporidium .............................................................................................. 8 Life cycle of Cryptosporidium .................................................................................................... 9 Cryptosporidium genomes ........................................................................................................ 11 General apicomplexan motility and invasion ............................................................................ 12 Rhomboid proteases .................................................................................................................. 13 Cryptosporidium invasion and development ............................................................................. 15 Mucin biology ........................................................................................................................... 17 Cryptosporidium adhesins ......................................................................................................... 21 Host immune response .............................................................................................................. 22 References ................................................................................................................................. 26 PAPER 1. GLYCOPROTEINS AND FREE GAL/GALNAC CAUSE CRYPTOSPORIDIUM TO SWITCH FROM AN INVASIVE SPOROZOITE TO A REPLICATIVE TROPHOZOITE ................................................................................................ 61 vii Abstract ..................................................................................................................................... 61 Introduction ............................................................................................................................... 62 Materials and methods .............................................................................................................. 64 Results ....................................................................................................................................... 66 Discussion ................................................................................................................................. 70 References ................................................................................................................................
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