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Functional Characterization of Leishmania Throughout in Vitro Biological Cycle: the Quest for a Quiescent Stage Among Amastigotes

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Functional Characterization of Leishmania Throughout in Vitro Biological Cycle: the Quest for a Quiescent Stage Among Amastigotes Faculty of Pharmacy, Biomedical and Veterinary Sciences Department of Biomedical Sciences Functional characterization of Leishmania throughout in vitro biological cycle: the quest for a quiescent stage among amastigotes Dissertation for the degree of Doctor in Biomedical Sciences at the University of Antwerp to be defended by Marlene Jara Portocarrero Promoters: Prof. Dr Jean-Claude Dujardin Prof. Dr. Jorge Arevalo Antwerp, 2019 Doctoral committee Chair Prof. Dr. Marleen Verhoye (University of Antwerp, Belgium) Member Prof. Dr. Paul Cos (University of Antwerp, Belgium) Prof. Dr. Kris Laukens (University of Antwerp, Belgium) Prof. Dr. Luc Kestens (University of Antwerp, Belgium) Prof. Dr. Michael Barrett (University of Glasgow) Prof. Dr. Michael Miles (London Centre for Neglected Tropical Disease Research) Promotors Prof. Dr. Jean-Claude Dujardin (Institute of Tropical Medicine, University of Antwerp, Belgium) Prof. Dr. Jorge Arevalo (Institute of tropical Medicine Alexander von Humboldt, UCPH, Lima, Peru) COLOFON Cover picture: Live cell imaging of peritoneal mouse macrophages infected with Leishmania mexicana. Dutch title Functionele karakterisering van Leishmania gedurende de gehele in vitro biologische cyclus: de zoektocht naar een slaaptoestand fase onder amastigoten. Acknowledgements I would like to thank my co-promotor Jorge Arevalo for fostering my interest in this peculiar pathogen called Leishmania throughout the years with interesting discussion and intriguing questions. However, doing a PhD was not on my mind therefore I would like to specially thank him and also to Manu Vanaerschot for encouraging me to pursue a PhD between the Institute of tropical Medicine Alexander von Humboldt (ITM AvH) and the Institute of Tropical Medicine of Antwerp (ITM) in the laboratory of Jean Claude. I would like to specially thank Jean Claude for hosting me on his laboratory, he has been my direct supervisor and co-promotor at ITM. I own him the materialization of an adventurous PhD proposal that was written and submitted under his wings. I would like to thank both Jorge Arevalo and Jean Claude because without their commitment, enthusiasm and continuous support this PhD project would have not been in the state it is today. I also would like to thank Jean Claude because apart from all the science, he taught me research involves a lot of marketing and collaborative work. Thank you very much Jean Claude for been a patient, kind and empathic big boss. This work would have not been possible without the support of all my colleagues that were or are part of the Department of Biomedical Science at the Institute of Tropical Medicine of Antwerp. Thank you very much to Bart Cuypers and Maya Berg for the team work regarding metabolomics. Extra thanks to Bart who helped me with the Dutch translation of the summary of this thesis. Thank you very much to Guy Caljon and Geraldine for their guidance in animal models and confocal mycroscopy respectively. I would like to express my special gratitude to Ilse Maes for her help with diverse matters she was always giving me assistance since my first arrival in 2014 up today. Thank you very much to Hideo Imamura for his advice with all the matters related with Leishmania genomes and his cheerful Hi5. Thanks also to Ann Ceulemans for her always kind and enthusiastic guidance at the Flow Cytometry facility. Thanks to the important help of Jeroem Swiers and Luc Verhelst in the cryobank and the animal facility respectively. Thank you very much to Aya who was there to grab a coffee and listen my concerns during the down periods of my PhD. Moreover. I would also like to thank all the members of the MPU unit for the input and interesting discussions in our weekly meetings. I would also like to express special thanks to Braulio Valencia and Andrea Boggild for the collaborative work during the recruiting and follow up of patients with mucosal leishmaniasis. Without them the clinical work would not have been possible. My gratitude also to Milena Alba for performing the molecular diagnostic and tipification of Leishmania. Unfortunately, research cannot be done without money. Therefore, this PhD project would not have been feasible without the institutions that provided funds for my fellowship and/or consumables: the Belgian Directorate General for Development Cooperation-DGDC (framework agreement 3.III and 4) and the Department of Economy, Science and Innovation in Flanders project (ITM-SOFIB, SINGLE). Thanks also to the administrators of these projects either in Lima or in Antwerp: Sabine Desager, Martha Stas, De Smet Sieglinde and Miguel Angel Peña. I can not to forget to acknowledge all the people at “beer time” and among their more loyal attendants: Adam, Conor, Achileas, Laura, Kara, Vera, Nandini, Nico and Franck. It was always a stress relief the often-absurd discussions ruling our table. I would like to thank my mother and friends who have always been encouraging and supportive. Sandra, Christopher, Ana y Carlos ustedes me dieron aliento en los momentos que más lo necesitaba. Finally, I would like to thank Ina for all her understanding and the ”switching of” adventures we had together. Having you on my side makes me feel extremely lucky. Table of contents Chapter 1: Leishmania & Leishmaniasis………… .............................................................. 17 1.1. Leishmania taxonomy and life cycle .............................................................. 19 1.2. Epidemiology .................................................................................................. 20 1.3. Clinical manifestations ................................................................................... 23 1.3.1. Cutaneous leishmanaisis ........................................................................ 25 1.3.2. Mucosal leishmaniasis ............................................................................ 26 1.3.3. Visceral leishmaniasis ............................................................................. 26 1.3.4. Post kala-azar dermal leishmaniasis....................................................... 27 1.4. Diagnosis ........................................................................................................ 28 1.5. Treatment of leishmaniasis and therapeutic failure ...................................... 29 1.5.1. Pentavalent antimonials ......................................................................... 29 1.5.2. Amphotericin B ....................................................................................... 32 1.5.3. Miltefosine ............................................................................................. 33 1.5.4. Paromomycin ......................................................................................... 34 1.6. Molecular traits of Leishmania ....................................................................... 36 1.6.1. Leishmania genome: nuclear and kinetoplast DNA ............................... 36 1.6.2. Ribosomal RNA ....................................................................................... 37 1.6.3. Transcription of nuclear genes in Leishmania ........................................ 38 1.7. References ...................................................................................................... 41 Chapter 2: Leishmania surviving abilities and adaptive skills ........................................ 53 2.1. Adaptation to establish the infection of macrophages .................................. 55 2.1.1. Promastigotes adaptation to survive the process of phagocytosis: ...... 56 2.1.2. Early modulation of the immune response ............................................ 58 2.2. Morphological and metabolic changes through the differentiation of promastigotes to amastigotes ................................................................................... 60 2.3. Amastigotes adaptations to maintain the host infection .............................. 62 2.3.1. The fight for nutrients involved in the Redox metabolism: ................... 63 2.3.2. Modulation of the adaptive immune response ..................................... 64 2.4. Quiescence and Leishmania .......................................................................... 68 2.4.1. Generalities about persistence, latency, dormancy and quiescence .... 68 2.5. Quiescence in Leishmania ............................................................................. 70 2.6. References ..................................................................................................... 72 Chapter 3: Rationale, hypothesis and objectives .......................................................... 85 3.1. Rationale ........................................................................................................ 87 3.2. Working hypothesis ....................................................................................... 88 3.3. Main and secondary research objectives ...................................................... 88 3.3.1. Main Objective....................................................................................... 88 3.3.2. Secondary objectives ............................................................................. 89 3.4. Research methodology .................................................................................. 89 3.5. References ..................................................................................................... 93 Chapter 4: Quantitative kinetoplast DNA assessment during treatment of mucosal Leishmaniasis
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