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Stockage up Edel Nuxeo Université de Poitiers Faculté de Médecine et de Pharmacie ANNÉE 2019 Thèse n° THÈSE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR EN PHARMACIE (Arrêté du 17 juillet 1987) et MÉMOIRE DU DIPLÔME D’ÉTUDES SPÉCIALISÉES DE BIOLOGIE MÉDICALE (Décret 88-996 du 19 octobre 1988) présentée et soutenue publiquement le 20 mai 2019 à NANTES par Mademoiselle IRIMIA Alix Dynamique de réplication des torque teno virus dans une cohorte de patients cérébro-lésés Composition du jury : Président : Monsieur le Professeur LEVEQUE Nicolas, PU-PH, CHU de Poitiers Membres : Madame le Professeur IMBERT Berthe-Marie, PU-PH, CHU de Nantes Monsieur le Professeur ROQUILLY Antoine, PU-PH, CHU de Nantes Madame le Docteur COSTE-BUREL Marianne, PH, CHU de Nantes Directeur de thèse : Madame le Docteur BRESSOLLETTE-BODIN Céline, MCU-PH, CHU de Nantes Université de Poitiers Faculté de Médecine et de Pharmacie ANNÉE 2019 Thèse n° THÈSE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR EN PHARMACIE (Arrêté du 17 juillet 1987) et MÉMOIRE DU DIPLÔME D’ÉTUDES SPÉCIALISÉES DE BIOLOGIE MÉDICALE (Décret 88-996 du 19 octobre 1988) présentée et soutenue publiquement le 20 mai 2019 à NANTES par Mademoiselle IRIMIA Alix Dynamique de réplication des torque teno virus dans une cohorte de patients cérébro-lésés Composition du jury : Président : Monsieur le Professeur LEVEQUE Nicolas, PU-PH, CHU de Poitiers Membres : Madame le Professeur IMBERT Berthe-Marie, PU-PH, CHU de Nantes Monsieur le Professeur ROQUILLY Antoine, PU-PH, CHU de Nantes Madame le Docteur COSTE-BUREL Marianne, PH, CHU de Nantes Directeur de thèse : Madame le Docteur BRESSOLLETTE-BODIN Céline, MCU-PH, CHU de Nantes 2 UNIVERSITE DE POITIERS Faculté de Médecine et de Pharmacie Année universitaire 2018-2019 PHARMACIE Professeurs ➢ CARATO Pascal, Chimie Thérapeutique ➢ PAIN Stéphanie, Toxicologie (HDR) ➢ COUET William, Pharmacie Clinique ➢ RIOUX BILAN Agnès, Biochimie ➢ DUPUIS Antoine, Pharmacie Clinique ➢ TEWES Frédéric, Chimie et Pharmaco chimie ➢ FAUCONNEAU Bernard, Toxicologie ➢ THEVENOT Sarah, Hygiène et Santé publique ➢ GUILLARD Jérôme, Pharmaco chimie ➢ THOREAU Vincent, Biologie Cellulaire ➢ IMBERT Christine, Parasitologie ➢ WAHL Anne, Pharmaco chimie, Produits naturels ➢ MARCHAND Sandrine, Pharmacocinétique ➢ OLIVIER Jean Christophe, Galénique AHU ➢ PAGE Guylène, Biologie Cellulaire ➢ BINSON Guillaume ➢ RABOUAN Sylvie, Chimie Physique, Chimie Analytique ➢ RAGOT Stéphanie, Santé Publique PAST - Maître de Conférences Associé ➢ SARROUILHE Denis, Physiologie ➢ DELOFFRE Clément, Pharmacien ➢ SEGUIN François, Biophysique, Biomathématiques ➢ HOUNKANLIN Lydwin, Pharmacien Maîtres de Conférences Professeur 2nd degré ➢ BARRA Anne, Immunologie-Hématologie ➢ DEBAIL Didier ➢ BARRIER Laurence, Biochimie ➢ GAY Julie ➢ BODET Charles, Bactériologie (HDR) ➢ BON Delphine, Biophysique Poste de Doctorant ➢ BRILLAULT Julien, Pharmacologie ➢ FREYSSIN Aline ➢ BUYCK Julien, Microbiologie ➢ CHARVET Caroline, Physiologie ➢ DEBORDE Marie, Sciences Physico-Chimiques ➢ DELAGE Jacques, Biomathématiques, Biophysique ➢ FAVOT Laure, Biologie Cellulaire et Moléculaire ➢ GIRARDOT Marion, pharmacognosie, botanique, biodiversité végétale ➢ GREGOIRE Nicolas, Pharmacologie (HDR) ➢ HUSSAIN Didja, Pharmacie Galénique (HDR) ➢ INGRAND Sabrina, Toxicologie ➢ MARIVINGT-MOUNIR Cécile Pharmaco chimie 3 4 5 Remerciements A Monsieur le Professeur Nicolas Lévêque, vous me faites l’honneur de présider ce jury, veuillez trouver ici l’expression de mon profond respect. A Madame le Docteur Céline Bressollette-Bodin, pour m’avoir confié ce travail, je te remercie pour tous tes conseils et ton soutien. A Madame le Professeur Berthe-Marie Imbert, vous me faites l’honneur de juger ce travail, veuillez trouver ici mes sincères remerciements. A Monsieur le Professeur Antoine Roquilly, vous me faites l’honneur de juger ce travail, veuillez trouver ici mes sincères remerciements. A Madame le Docteur Marianne Coste-Burel, pour me faire l’honneur de juger ce travail, merci pour tous tes conseils techniques et pour ton soutien lors des JNI. A Madame le Docteur Louise Castain, pour avoir pris le temps de m’aider dans la rédaction de ce manuscrit, merci pour tous tes conseils. A toute l’équipe du laboratoire de Virologie du CHU de Nantes, pour leur savoir-faire et leur bonne humeur au quotidien. A toutes les équipes que j’ai pu rencontrer pendant mon internat à Poitiers et à Nantes. A tous mes co-internes, A Camille, merci pour tout ton soutien au cours de cette dernière ligne droite. A Sophie, Anne, Anaïs, Coralie, Adeline et tous les autres pour tous ces bons moments durant notre internat. A mes amis, pour tous les bons moments passés ensembles. 6 A toute ma famille, A mes parents, pour leur soutien infaillible depuis toujours. A mes sœurs, Marie et Lucile, pour tous nos moments partagés et ceux à venir. A Ronan, parce que la vie est plus belle avec un chapeau sur la tête, merci pour tout… 7 Table des matières Liste des abréviations ............................................................................................................... 11 Liste des figures ....................................................................................................................... 13 Liste des tableaux ..................................................................................................................... 15 Première partie : Bibliographie ................................................................................................ 16 I. Le virome ..................................................................................................................... 16 II. Les torque teno virus .................................................................................................... 17 A. Circonstances de découverte et historique des TTV .............................................. 17 B. Classification et taxonomie virale .......................................................................... 18 C. La particule virale .................................................................................................. 19 1. Structure de la particule virale ........................................................................... 19 2. Organisation génomique .................................................................................... 20 D. Cycle de réplication ............................................................................................... 21 1. Synthèse des ARN messagers ............................................................................ 21 2. Expression et fonction des protéines virales ...................................................... 22 a. Expression protéique ...................................................................................... 22 b. Fonctions des protéines virales ....................................................................... 23 3. Cycle de réplication ............................................................................................ 24 E. Variabilité génétique .............................................................................................. 25 F. Epidémiologie et pouvoir pathogène ..................................................................... 27 1. Epidémiologie .................................................................................................... 27 a. Prévalence ....................................................................................................... 27 b. Répartition géographique ............................................................................... 29 c. Transmission ................................................................................................... 29 2. Pouvoir pathogène .............................................................................................. 30 a. Pathologies hépatiques ................................................................................... 30 b. Pathologies respiratoires ................................................................................. 31 c. Cancers et pathologies hématologiques .......................................................... 31 d. Pathologies auto-immunes .............................................................................. 31 G. Lien entre TTV et système immunitaire ................................................................ 32 1. Evolution du virome et de la part des Anellovirus en fonction du statut immunitaire .................................................................................................................. 32 8 2. Etude des TTV chez les patients immunodéprimés ........................................... 35 a. Méthodes de détection et de quantification de l’ADN des TTV .................... 35 b. Cinétique de réplication des TTV chez les patients immunodéprimés .......... 37 III. L’immunodépression post-traumatique .................................................................... 40 A. Physiopathologie .................................................................................................... 40 1. Rappels sur l’immunité innée ............................................................................. 40 2. Réponse immunitaire post-traumatique ............................................................. 42 B. Infections et réactivations virales en réanimation .................................................. 44 Deuxième partie : Travail personnel ........................................................................................ 45 I. Objectifs ......................................................................................................................
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