Cholera Thesis MOORE

UNIVERSITE D’AIX-MARSEILLE ECOLE DOCTORALE SCIENCE DE LA VIE ET DE LA SANTE Faculté de Pharmacie LABORATORY: UMR MD3 – parasite infections: transmission et treatment Laboratory of Parasitology-Mycology – APHM Discipline: Human pathology – Specialty: Infectious diseases Scientific domain - Department of biology, medicine and health Thesis prepared within the framework of the Public Health Doctoral Network, led by the EHESP Thesis presented to obtain a PhD from Aix-Marseille University By Ms. Sandra MOORE born 17/02/1977 in Worcester, Massachusetts, United States of America Dynamics of Cholera Epidemics in Haiti and Africa Defense on December 13, 2016 at 1PM before the jury as follows: Dr. Renaud PIARROUX Thesis director UMR MD3, Aix-Marseille Université Assistance-Publique Hôpitaux de Marseille Dr. Jean GAUDART Co-director UMR 912 SESSTIM Aix-Marseille Université Dr. Martine Wallon Rapporteur Centre Hospitalier Universitaire de Lyon Hôpital de la Croix-Rousse Dr. François-Xavier Weill Rapporteur Institut Pasteur, Paris Dr. Laurence Lachaud President Centre Hospitalier Universitaire de Montpellier Université Montpellier 1 1 Acknowledgments First I would like to thank my thesis director, Professor Renaud PIARROUX, who was the only to take me under his wing when I was searching for an institution in which to carry out my MPH internship. The entire staff at the EHESP, especially Judith MÜLLER, for funding my PhD, guiding through the PhD process, offering a variety of interesting courses and providing an enriching environment and network of public health students and professionals. My “rapporteurs de these” for agreeing to revise my work, Dr. Martine WALLON and Dr. Francois-Xavier WEILL. Thank you to Dr. Laurence LACHAUD for agreeing to be president of the jury. Merci beaucoup!! I would like to thank Dr. Jean GAUDART, my thesis co-director, for helping me with the transition between Master of Public Health and PhD as well as your support throughout my PhD. I would like to thank the entire Parasitology-Mycology laboratory, especially: - Stanislas REBAUDET - who graciously to took the time to explain everything to me, although I do not believe his explanation of pollution for the magnificent sunsets of Marseille ;) - Martine PIARROUX - for explaining the ins and outs of cartography and helping me each time I was in a crunch. - Anne Cécile NORMAND – my official French teacher and secretary for all those dreaded phone calls in French. - Lindsay OSEI –for helping me with the Ghana project and eventually taking over as I leave! - Stephane RANQUE – for letting me settle into his already very crowded office, conversations in French, English and German and all those medical certificates for my swimming competitions. - Fakhri JEDDI - fellow PhD student and neighbor – thanks for all the discussions! 2 - Bella TOGA – thanks for the walks, runs and chats – we’ll go on the boat soon! - Farid DJENAD – for helping me with my endless computer problems. I still never managed to work with WORD and internet at the same time because of the firewall L - Mohammed Hashim AL-YASIRI – for always being there to answer my questions while also struggling through the PhD, all while working without a proper office or desk. - Joelle BAYLE for managing the laboratory amazingly well. - Nicolas, Jérémy, Christine, Corinne, Nicole and all the other technicians and staff ! To Jessica DUNOYER and Francois BELLET at UNICEF WCARO – thanks a million for all that you have done for our mission to Ghana, Togo and Benin! Speaking of the 2014 mission, I would also like thank Paul COTTAVOZ for accompanying me in Ghana, Togo and Benin - your insight and experience was priceless!! At the Wellcome Trust Sanger Institute, I would like to especially thank Nicholas THOMSON and Ankur MUTREJA for working with us since the beginning; and to Maria FOOKES for helping with the last set of genomic analyses and teaching me about phylogeny during my stay in Hinxton. At the L’Hopital d'Instruction des Armées Laveran in Marseille, I would like to thank Eric GARNOTEL, Hélène THEFENNE, Jean-Jacques DEPINA, and Gilles GBAGUIDI for all your help conserving, growing and attempting to isolate DNA from my Vibrio cholerae isolates! I would like to thank Guillaume CONSTANTIN DE MAGNY for many interesting discussions and your assistance with the study of cholera in West Africa. I also thank Amy Gassama SOW for your assistance with the V. cholerae strains from Senegal. 3 In Cote d’Ivoire, I would like to extend my thanks to Bisimwa RUHANA MIRINDI. We tried… In Ghana, I would like to especially thank Enoch OFOSU, Bismarck DINKO, Anthony Zunuo DONGDEM, David OPARE, Emmanuel DZOTSI, Badu Sarkodie, Michael DOGBE, Gideon KYE-DUODU, Frank NYONATOR, Fred BINKA, John TAMPUORI, Kweku QUANSAH, Lawrence Henry OFOSU-APPIAH, Lorreta ANTWI, Ashon ATO, James ADDO, Bernard Bright DAVIES-TEYE, John ELEEZA, Jonas AMANU, Rosemary GBADZIDA, Joseph Kwami DEGLEY, Anthony KARIKARI, Atsu SEAKE-KWAWU, Samuel AMOAKO- MENSAH, Kassim Yakubu AL-HASSAN, David DUNCAN, and Daniel YAYEMAIN. In Togo I would like to thank Adodo YAO SADJI, Bawimodom BIDJADA, Ouyi Tante VALENTIN, Stanislas TAMEKLOE, Kossivi Agbelenko AFANVI, Balanhewa AGUEM- MASSINA, Amidou SANI, Kwoami DOVI, Isselmou BOUKHARY, Fataou SALAMI, Tagba ASSIH, and Magali ROMEDENNE. In Benin I extend thanks to Clément Kakaï GLÈLÈ, Gregoire ADADJA, Nadine AGOSSA, Adjakidje Senami AUREL, Honore BANKOLE, Francois HOUNSOU, Agnes HOUNWANOU, Mamadou Mouctar BALDÉ, Isabelle SÉVÉDÉ-BARDEM, Adama OUEDRAOGO and Wilfried HOUETO. Concerning the analysis of the transborder cholera epidemic that affected Guinea and Sierra Leone in 2012, I would like to thank Lamine KOIVOGUI, Sakoba KEITA, Amara JAMBAI, Leonard HEYERDAHL, and H DIALLO. In the Democratic Republic of the Congo I extend my gratitude to Berthe MIWANDA, Didier BOMPANGUE, Aaron ARUNA ABEDI, and Jean-Jacques MUYEMBE. I also extend thanks to Raymond RUIMY, Hilde DE BOECK, and Pierre-Denis PLISNIER. To Tina and Michael – thanks for helping me to discover Africa with our trip to Rwanda. 4 Thanks to Dustin ROBERTSON, without you, I would have never been able to do this. All the swimmers of Team Malmousque with whom we shared magical escape of everyday stresses by swimming kilometers of the magnificent Marseille coast and the islands. Fabien, Bruno, Christophe, JP, Tbox, Dani, Yvan, Cyril, JeanLuc, Bernard, Vince, Manu, etc. Without my aquatic friends, the fish and our underwater world, I wouldn’t have survived the recent death of my father, never mind the pursuit of a PhD. A special thanks to my best friend Areti for allows being there - Σε αγαπώ. My mother, my sisters Sheryl and Caroline, my brother John, my niece Samia, Uncle Skip and all other family and friends on the other side of the Atlantic Ocean, thanks for your support and understanding of my need to wander and explore. 5 I dedicate this work to my dad and my grandfather. 6 Table of contents 1 ACKNOWLEDGMENTS 2 2 LIST OF PUBLICATIONS INCLUDED IN THE THESIS 9 3 ABSTRACT 10 4 RESUME 11 5 INTRODUCTION 13 5.1 CHOLERA OVERVIEW 13 5.2 V. CHOLERAE CLASSIFICATION 16 5.3 INFECTION AND CLINICAL ASPECTS OF CHOLERA 17 5.3.1 INFECTION 17 5.3.2 CLINICAL SYMPTOMS, DIAGNOSIS AND TREATMENT 17 5.3.3 CHOLERA RISK FACTORS 18 5.3.4 PREVENTION 19 5.4 ECOLOGY AND LIFE CYCLE OF V. CHOLERAE 20 5.5 THE SEVENTH CHOLERA PANDEMIC IN HAITI AND AFRICA (DEMOCRATIC REPUBLIC OF THE CONGO AND WEST AFRICA) 21 5.5.1 CHOLERA IN HAITI 21 5.5.2 CHOLERA IN AFRICA 22 6 RESEARCH QUESTION 25 7 AIMS AND OBJECTIVES 28 8 WIDESPREAD EPIDEMIC CHOLERA DUE TO A RESTRICTED SUBSET OF VIBRIO CHOLERAE CLONES 31 9 CHOLERA IN HAITI 41 9.1 NO EVIDENCE OF SIGNIFICANT LEVELS OF TOXIGENIC V. CHOLERAE O1 IN THE HAITIAN AQUATIC ENVIRONMENT DURING THE 2012 RAINY SEASON 42 9.1.1 INTRODUCTION 42 9.1.2 MATERIALS AND METHODS 44 9.1.3 RESULTS 51 9.1.4 DISCUSSION 54 9.2 THE DRY SEASON IN HAITI: A WINDOW OF OPPORTUNITY TO ELIMINATE CHOLERA 60 9.2.1 INTRODUCTION 60 9.2.2 METHODS 62 9.2.3 RESULTS 64 9.2.4 DISCUSSION 71 9.2.5 CONCLUSION 75 10 ANALYSIS OF V. CHOLERAE ISOLATES FROM THE DEMOCRATIC REPUBLIC OF THE CONGO 76 10.1 INTEGRATED ANALYSIS OF ANTIBIOTIC SUSCEPTIBILITY AND GENETIC PROFILES OF 1093 VIBRIO CHOLERAE ISOLATES FROM THE DEMOCRATIC REPUBLIC OF THE CONGO 77 10.1.1 THE STUDY 77 7 10.1.2 CONCLUSIONS 82 10.2 RELATIONSHIP BETWEEN DISTINCT AFRICAN CHOLERA EPIDEMICS REVEALED VIA MLVA HAPLOTYPING OF 337 VIBRIO CHOLERAE ISOLATES 84 10.2.1 INTRODUCTION 84 10.2.2 MATERIALS AND METHODS 85 10.2.3 RESULTS 92 10.2.4 DISCUSSION 100 10.2.5 SUPPORTING INFORMATION 103 11 INTEGRATED STUDY OF CHOLERA EPIDEMICS IN WEST AFRICA 111 11.1 DIRECT DRIED STOOL SAMPLING ON FILTER PAPER FOR MOLECULAR ANALYSES OF CHOLERA 112 11.2 DYNAMICS OF CHOLERA EPIDEMICS IN WEST AFRICA 116 11.2.1 INTRODUCTION 116 11.2.2 METHODS 118 11.2.3 RESULTS 120 11.2.4 DISCUSSION 127 11.2.5 SUPPLEMENTARY FILES 130 12 CONCLUSION 136 13 FUTURE DIRECTIONS 156 14 REFERENCES 158 8 2 List of publications included in the thesis Listed in order of appearance: 1 - Moore, S, N Thomson, A Mutreja, and R Piarroux. 2014. “Widespread Epidemic Cholera Caused by a Restricted Subset of Vibrio Cholerae Clones.” Clinical Microbiology and Infection 20 (5). European Society of Clinical Infectious Diseases: 373–79. doi:10.1111/1469-0691.12610. 2 - Baron, Sandrine, Jean Lesne, Sandra Moore, Emmanuel Rossignol, Stanislas Rebaudet, Pierre Gazin, Robert Barrais, Roc Magloire, Jacques Boncy, and Renaud Piarroux. 2013. “No Evidence of Significant Levels of Toxigenic V. Cholerae O1 in the Haitian Aquatic Environment During the 2012 Rainy Season.” PLOS Currents Outbreaks Sept 13: 1–14.

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