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Ecological, epidemiological, and molecular drivers of cross- species pathogen transmission among humans and non-human primates: from malaria to rhinovirus The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Scully, Erik John. 2018. Ecological, epidemiological, and molecular drivers of cross-species pathogen transmission among humans and non-human primates: from malaria to rhinovirus. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41129224 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Ecological, epidemiological, and molecular drivers of cross-species pathogen transmission among humans and non-human primates: from malaria to rhinovirus A dissertation presented by Erik John Scully to The Department of Human Evolutionary Biology in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Human Evolutionary Biology Harvard University Cambridge, Massachusetts May 2018 © 2018 – Erik John Scully All rights reserved. Dissertation Advisor: Richard W. Wrangham Erik John Scully Ecological, epidemiological, and molecular drivers of cross-species pathogen transmission among humans and non-human primates: from malaria to rhinovirus Abstract Malaria constitutes a major source of human mortality and morbidity worldwide. Although the bulk of this public health burden is caused by four human-adapted parasite species, these represent less than 1% of the malaria parasite diversity found in the natural world. The expansion of human populations into biodiversity hotspots has elevated exposure to novel malaria parasites, and evidence of primate-to-human transmission has begun to accumulate. There now exists a tangible public health imperative to critically evaluate the ecological and molecular mechanisms governing the host-specificity of malaria parasites in order to identify which species pose a material threat to human populations. The purpose of this dissertation is to elucidate the ecological, epidemiological, and molecular variables that govern the transmission of infectious diseases among humans and non-human primates. In Chapter 1, I provide a conceptual framework for zoonotic disease emergence and discuss the ecological and molecular barriers to cross-species transmission of malaria parasites. In Chapter 2, we quantify the ecological drivers of malaria transmission among wild chimpanzee hosts in equatorial Africa and map spatiotemporal variation in the risk that these parasites pose to local human populations. In Chapters 3 and 4, we review the molecular mechanisms governing the host-specificity of non-human primate malaria parasites and develop a method for the generation of immortalized erythroid progenitor cell lines from small volumes of peripheral blood, offering a genetically tractable model system for studies of malaria host-specificity. In Chapter 5, we identify human rhinovirus C as the cause of a lethal respiratory outbreak in a community of wild chimpanzees in western Uganda and demonstrate a species-wide genetic susceptibility to this virus, underscoring the profound conservation implications of human-to-ape virus transmission. In Chapter 6, I conclude the dissertation by discussing non-human primate malaria parasite diversity in the context of global health and review historical and contemporary evidence of malaria cross-species transmission. It is ! iii my hope that the studies presented in this dissertation will catalyze cooperation among stakeholders in the public health and scientific research communities by highlighting malaria zoonosis as a topic that warrants further consideration in discussions of malaria eradication. ! iv Acknowledgments This dissertation would not have been possible without the assistance and generosity of numerous people to whom I am very grateful. First, I want to thank Richard Wrangham, my doctoral dissertation advisor, whose passion for primatology and the natural world kindled my interest in chimpanzee ecology and behavior before I had even enrolled in the program. I will be eternally grateful to Richard for encouraging me to pursue a doctoral degree at Harvard and for facilitating the numerous collaborations that came to characterize my doctoral research. Not only is Richard a brilliant and rigorous scientist, but he is also an extremely generous and compassionate person. Next, I want to express my sincere gratitude to Manoj Duraisingh, who catalyzed my interest in the molecular biology of malaria parasites. Manoj’s boundless enthusiasm for malaria research is unmatched by anyone I have encountered, and his capacity to see the larger picture is an enviable quality. Manoj welcomed me into his lab just as my interest in malaria zoonoses began to consume my dissertation research. My foray into functional genetics would have likely been unsuccessful without the tools, resources, expertise, and summer barbecues that Manoj offered. I am also keen to thank the Kibale Chimpanzee Project and the Makerere University Biological Field Station, which offered a home in western Uganda during my dissertation fieldwork. Emily Otali’s wit and expertise were critical in navigating my research permits and permissions within Uganda, and Zarin Machanda, Melissa Emery Thompson, and Martin Muller helped me to coordinate issues ranging from the collection of fecal samples to the allocation of field assistant bonuses. Zarin also provided extensive feedback on multiple projects related to chimpanzee behavioral ecology. Finally, I want to thank each of my Ugandan field assistants for offering both companionship and expertise during fieldwork in Kibale. Without the longitudinal dataset cultivated by these field assistants, Chapter 2 of this dissertation would not have been possible. I would be remiss if I did not thank all of the professors who facilitated my dissertation research and shaped my academic interests. Before I enrolled at Harvard, my Master’s thesis advisor, Robert Curry, ! v played an instrumental role in cultivating my decision to pursue a career in the biological sciences. I am also very grateful to Beatrice Hahn for inviting me to screen my chimpanzee samples in her University of Pennsylvania laboratory. I want to thank Harvard’s Department of Human Evolutionary Biology, especially Terence Capellini and Maryellen Ruvolo for providing feedback on my developing research projects at multiple points during my dissertation. Charlie Nunn and Bill Hanage catalyzed my interest in the evolutionary dynamics of infectious disease. Dan Neafsey facilitated my Broadnext10 grant and was always willing to discuss elements of my research. Caroline Buckee encouraged me to adopt a mathematical approach to infectious disease transmission and Flaminia Catteruccia highlighted the critical role that the mosquito plays in malaria transmission. Tony Goldberg provided valuable insight into topics related to zoonotic disease and his feedback greatly improved this dissertation. I would also like to thank Charlotte Rasmussen and the World Health Organization for taking an interest in my dissertation research and for cultivating its translational applications. Numerous graduate students and post-doctoral researchers played a critical role in the development of my dissertation by offering both academic feedback and personal friendship over the course of my tenure in the program. In the Wrangham Lab, Andy Cunningham, Luke Glowacki, Manvir Singh, Collin McCabe, and Stephanie Meredith provided feedback on projects related to the ecology of non-human primate malaria parasites. In the Duraisingh Lab, Estela Shabani, Usheer Kanjee, Christof Gruring, Mudit Chaand, Martha Clark, Gabe Rangel, Jon Goldberg, Selasi Dankwa, Natasha Archer, Christina Moreira, Caroline Keroack, Brendan Elsworth, Deepali Ravel, Aditya Paul, Rebecca Lee, Katy Shaw Saliba, Kristen Skillman, Caeul Lim, Markus Ganter, and Venee Tubman helped to mold ideas concerning the epidemiology and molecular biology of malaria zoonoses. Drew Enigk provided much needed companionship during multiple summers in western Uganda. This dissertation would not have been possible without grants and fellowships from the National Science Foundation, the Broad Institute, the National Geographic Society, the National Institutes of Health, the International Primatological Society, Harvard University, and the Cora DuBois Charitable Trust. Finally, and most importantly, I wish to express my most sincere gratitude to my family for offering ! vi unrelenting support and encouragement throughout my academic pursuits. I first want to thank my mother, Margaret, and my father, Erik V., for imploring me to follow my dreams and for indulging late night conversations about esoteric biological topics across the campfire in western Pennsylvania. I am grateful to my brother, Ryan, and my sister, Meghan, for helping me to see the bigger picture and for providing comic relief. Above all, I want to thank my wife, Claire, who has made everything possible. From studying vegetarian spiders on the Yucatan Peninsula in Mexico to tracking zoonotic diseases in western Uganda, Claire has always supported my unconventional interests and has encouraged me to pursue truth. Claire’s intellectual fortitude