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Caractérisation De Nouveaux Gènes Et Polymorphismes Potentiellement Impliqués Dans Les Interactions Hôtes-Pathogènes

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Caractérisation De Nouveaux Gènes Et Polymorphismes Potentiellement Impliqués Dans Les Interactions Hôtes-Pathogènes Aix-Marseille Université, Faculté de Médecine de Marseille Ecole Doctorale des Sciences de la Vie et de la Santé THÈSE DE DOCTORAT Présentée par Charbel ABOU-KHATER Date et lieu de naissance: 08-Juilllet-1990, Zahlé, LIBAN En vue de l’obtention du grade de Docteur de l’Université d’Aix-Marseille Mention: Biologie, Spécialité: Microbiologie Caractérisation de nouveaux gènes et polymorphismes potentiellement impliqués dans les interactions hôtes-pathogènes Publiquement soutenue le 5 Juillet 2017 devant le jury composé de : Pr. Daniel OLIVE Directeur de Thèse Pr. Brigitte CROUAU-ROY Rapporteur Dr. Benoît FAVIER Rapporteur Dr. Pierre PONTAROTTI Examinateur Thèse codirigée par Pr. Daniel OLIVE et Dr Laurent ABI-RACHED Laboratoires d’accueil URMITE Research Unit on Emerging Infectious and Tropical Diseases, UMR 6236, Faculty of Medicine, 27, Boulevard Jean Moulin, 13385 Marseille, France CRCM, Centre de Recherche en Cancérologie de Marseille,Inserm 1068, 27 Boulevard Leï Roure, BP 30059, 13273 Marseille Cedex 09, France 2 Acknowledgements First and foremost, praises and thanks to God, Holy Mighty, Holy Immortal, All-Holy Trinity, for His showers of blessings throughout my whole life and to whom I owe my very existence. Glory to the Father, and to the Son, and to the Holy Spirit: now and ever and unto ages of ages. I would like to express my sincere gratitude to my advisors Prof. Daniel Olive and Dr. Laurent Abi-Rached, for the continuous support, for their patience, motivation, and immense knowledge. Someday, I hope to be just like you. A special thanks to my “Godfather” who perfectly fulfilled his role, Dr. Pierre Pontarotti for his continuous daily support. Dr. Pontarotti was always there to listen and to give advice. He showed me different ways in research problem and the need to be persistent to accomplish any goal. I want to thanks Prof. Didier Raoult and Mediterranean Infection for the funding and making my PhD experience productive and stimulating. I am heartily thankful to Marie-Hélène, for being an excellent “mother substitute” during all these years. Without her encouragement and constant support I could not have finished this work. I would also like to thank all of my Indian friends in the lab: Vivek, Vikas, Jai, Dhamo, Sourabh, Arup, Sweta for all their support in all situations. You were such great ambassadors of your beloved mother India. I thank my other fellow lab mates in both EBM and CRCM labs for the stimulating discussions, motivation and laughs during all these years. Special thanks to Sandrine, Marine, Olivier, Julien, Hassnae, Louis! Thanks for all your encouragement! I would like to thank my Lebanese friends and compatriots for accepting nothing less than excellence from me. I am also grateful to my family: Randa, Jean, Hoda, Chantal & Chris, because I owe it all to you. Many Thanks especially for your love, prayers and encouragement! Last but not the least, I would like to thank Carole, for supporting me throughout all these days... Distance never separates two hearts that really care! Thanks for your presence, your love and your ongoing prayers… Thank you for your patience on my moody days. Thank you for being my number one! I love you! Charbel 3 Table of Contents List of Abbreviations ................................................................................................................................ 7 Chapter 1: Introduction ........................................................................................................................... 9 I- Genetic susceptibility to infectious diseases ............................................................................. 10 1- Host-pathogen relationships after the Neolithic Revolution .................................................... 10 2- The host-pathogen co-evolution ............................................................................................... 11 3- Pathogens adapt to their host ................................................................................................... 12 4- Factors involved in host-pathogen interactions ........................................................................ 13 5- Resistance and susceptibility to infectious diseases ................................................................. 14 6- Genetic basis of infectious disease susceptibility in humans .................................................... 15 7- Twin studies demonstrate the importance of host genetic factors .......................................... 16 8- Examples of genetic susceptibilities to human infectious diseases .......................................... 17 9- Host adaptation, signatures of selection................................................................................... 19 II- Human genetic variations .......................................................................................................... 21 1- Major categories of human genetic variation ....................................................................... 21 - Structural rearrangements .................................................................................................... 21 - Insertion and deletion events ............................................................................................... 21 - Copy number variation .......................................................................................................... 22 - Transposons and retrotransposons ....................................................................................... 22 - Single-base-pair changes ....................................................................................................... 22 2- NGS data: continuously improving technologies .................................................................. 23 III- Features of immunity genes .................................................................................................. 27 IV- HLA, the extraordinary level of diversity ............................................................................... 28 Main objective ....................................................................................................................................... 31 Chapter 2: Materials and Methods ....................................................................................................... 32 1- Pipeline description ............................................................................................................... 33 Standard analysis ........................................................................................................................... 33 High sensitivity analysis ................................................................................................................. 34 Genotype verification .................................................................................................................... 34 Allele reconstructions .................................................................................................................... 34 2- Allotypes nomenclature ........................................................................................................ 35 4 3- Data sources .......................................................................................................................... 38 Chapter 3: Investigating the correlation between the SNP CT60 and coding variations in the CD28/CTLA4/ICOS gene region .............................................................................................................. 40 I- Investigating the diversity of these immunomodulatory genes in a set of individuals representing different populations ................................................................................................... 42 II- Investigating the coding diversity of 3 immunomodulatory genes (CD28, CTLA4, ICOS) in a set of individuals representing different populations............................................................................. 43 1- Material and methods ............................................................................................................... 43 2- Results ....................................................................................................................................... 44 III- Correlation between SNPs found in the coding regions of these genes and the SNP CT60 . 48 IV- Annex ..................................................................................................................................... 51 Chapter 4: Polymorphism and functional analysis of some immune genes controlling infection by Mycobacterium tuberculosis ................................................................................................................. 56 I- Introduction ............................................................................................................................... 57 II- Materials and methods ............................................................................................................. 58 III- RESULTS ................................................................................................................................. 59 1- TLR2 and Vitamin D pathway .................................................................................................... 59 Investigating the coding diversity of VDR and TLR2 in a set of individuals representing different populations .......................................................................................................................................
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