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Intérêt Des Primates Africains Dans La Recherche Sur Le Paludisme

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Intérêt Des Primates Africains Dans La Recherche Sur Le Paludisme ECOLE NATIONALE VETERINAIRE DE LYON Année 2006 - Thèse n° 25 INTÉRÊT DES PRIMATES AFRICAINS DANS LA RECHERCHE SUR LE PALUDISME THESE Présentée à l’UNIVERSITE CLAUDE-BERNARD - LYON I (Médecine - Pharmacie) et soutenue publiquement le 3 février 2006 pour obtenir le grade de Docteur Vétérinaire par SALLÉ Bettina Née le 4 octobre 1974 à Clermont de l’Oise ECOLE NATIONALE VETERINAIRE DE LYON Année 2006 - Thèse n° 25 INTÉRÊT DES PRIMATES AFRICAINS DANS LA RECHERCHE SUR LE PALUDISME THESE Présentée à l’UNIVERSITE CLAUDE-BERNARD - LYON I (Médecine - Pharmacie) et soutenue publiquement le 3 février 2006 pour obtenir le grade de Docteur Vétérinaire par SALLÉ Bettina Née le 4 octobre 1974 à Clermont de l’Oise Au Professeur PICOT, De la Faculté de Médecine Claude Bernard - Lyon I, Qui nous a fait l’honneur d’accepter la présidence de ce jury de thèse, Hommages respectueux. Au Professeur BOURDOISEAU De l’Ecole Nationale Vétérinaire de Lyon, Qui a accepté de diriger notre thèse à distance, Qu’il trouve ici l’expression de notre profonde reconnaissance. Au Professeur CADORÉ De l’Ecole Nationale Vétérinaire de Lyon, Qui a aimablement accepté de participer à notre jury de thèse, Qu’il trouve ici l’expression de nos sincères remerciements. Au Docteur Pierre ROUQUET, ex responsable du Centre de Primatologie du CIRMF, Pour son expérience, sa confiance, sa loyauté et son soutien. Longue route parmi la faune sauvage. Au Professeur Philippe BLOT, Directeur Général du CIRMF, Pour son accueil eu sein du centre et ses encouragements dans mes travaux. Salutations respectueuses. Au Docteur Pierre DRUILHE, Directeur de l’Unité de Parasitologie Biomédicale de l’Institut Pasteur, Pour le partage de ses connaissances et sa disponibilité. Sincères remerciements. Au Professeur Dominique MAZIER, Directrice de l’Unité Immunologie cellulaire et moléculaire des infections parasitaires de l’INSERM, Pour sa gentillesse et ses précieux conseils, Amicales salutations. Au Docteur Benjamin OLLOMO, chercheur en parasitologie au CIRMF, Pour m’avoir initiée aux méandres du paludisme. Salutations. A l’ensemble du personnel du Centre de Primatologie du CIRMF, Pour leur contribution toujours souriante à mon travail quotidien. Lévéléwé. A Nicole SALLÉ, Ma mère, ma Lumière. Pour son Amour inconditionnel. Pour ce qu’elle est. Mes plus belles émotions. A Magali, Marinette, Florent, Jean-Marie et leurs tribus respectives, Mon sang, mes ancres… Pour leur amour, sans limite, sans frontière. Mes plus tendres pensées. Au Docteur Émilie BAUDRY, Pour donner, chaque jour, ses lettres de noblesse à l’Amitié. Infinie tendresse. Aux Docteurs Véronique GONEL, Caroline JACQUES et Karin LEMBERGER, Pour ne pas avoir laisser les distances et les années ronger notre complicité. Amour, gloire et beauté. Aux Docteurs Bertrand LEMENERT, Olivier BISSEAUD, Christelle RIBOULET et Nathalie PALHA, Ô mes anciens, ô ma mère de clinique, Pour m’avoir sortie de la sombre ignorance et m’avoir initiée aux joies de notre métier. Reconnaissance éternelle. A Romain, Sandrine, Gilles, Olivier, Marie, Agnès, Paul, Trish, Valérie, Olivier, Sosthène, Isaac et les autres, gabonais de souche ou de cœur, Pour le partage de leur amour pour ce pays et pour ce continent. Tendresses. A mes étoiles et mes lunes, Pour avoir allumé mes nuits, coloré mes jours et fait mon cœur plus riche. Douceur caressante. A ces soleils rencontrés en terres rouges dont la lumière continue d’irradier de là-haut : Annelle, Esteban, Bettina, Bibiche. Tendres pensées, sourire en coin et cœur au bord des yeux. A tous ceux qui, pour quelques gènes de différence, nous offrent leur liberté et parfois leur vie pour rendre la nôtre plus facile. Respect et reconnaissance infinis. Au Docteur Jean-Louis SALLÉ, 22 février 1939 – 14 janvier 2000 Chirurgien de mon cœur, Pour m’avoir invitée dans cette Vie et avoir contribué à me la faire belle. Trois notes de blues. Evolution inéluctable qui, Parallèlement à ce grand courant Partant du singe pour aboutir à l’homme, Part de l’homme pour aboutir à l’imbécile. Boris Vian TABLE DES MATIERES Introduction ___________________________________________________ 17 PREMIERE PARTIE : BILAN ET ORIENTATION DE LA RECHERCHE SUR LE PALUDISME 17 A- SITUATION ACTUELLE DU PALUDISME _____________________________ 21 A.1- PRESENTATION ZOOLOGIQUE DU GENRE PLASMODIUM____________ 21 A.2- EPIDEMIOLOGIE DU PALUDISME__________________________________ 21 A.2.1- Importance du paludisme dans la santé publique_______________________ 21 A.2.2- Importances relatives des différentes espèces plasmodiales humaines ______ 23 A.2.3- Epidémiologie mondiale__________________________________________ 24 A.3- INFECTION ______________________________________________________ 27 A.3.1- Cycle du plasmodium____________________________________________ 27 A.3.2- Epidémiologie de la transmission___________________________________ 28 A.3.3- Clinique ______________________________________________________ 29 A.3.4- Diagnostic_____________________________________________________ 31 A.3.5- Thérapeutique__________________________________________________ 33 A.3.6- Prophylaxie____________________________________________________ 34 B- THEMATIQUES DE RECHERCHE SUR LE PALUDISME ________________ 35 B.1- PROBLEMATIQUE : LA COMPLEXITE INSOUPÇONNEE DU PALUDISME35 B.1.1- La complexité du plasmodium : polymorphisme et apparitions de résistance_ 35 B.1.2- La complexité de la relation hôte-parasite ____________________________ 37 B.1.3- Le coût des recherches ___________________________________________ 37 B.2- GRANDS AXES DE RECHERCHE SUR LE PALUDISME ________________ 38 B.2.1- Etude du génome du parasite ______________________________________ 38 B.2.2- Développement de la transgénèse __________________________________ 39 B.2.3- Phylogénie des plasmodiums ______________________________________ 40 B.2.4- Développement d’outils diagnostiques_______________________________ 43 B.2.5- Etudes de physiopathologie _______________________________________ 44 B.2.6- Etudes épidémiologiques _________________________________________ 44 B.2.7- Etude de l’immunité liée au paludisme ______________________________ 45 B.2.8- Etude des apparitions de résistance aux anti-paludiques _________________ 46 B.2.9- Développement de nouvelles stratégies thérapeutiques __________________ 48 B.2.10- Développement d’un vaccin antipaludique __________________________ 50 DEUXIEME PARTIE : LES PRIMATES AFRICAINS ET LA RECHERCHE SUR LE PALUDISME _____________________________________________________________ 57 A- UN POINT SUR L’UTILISATION DES PRIMATES NON-HUMAINS DANS LA RECHERCHE __________________________________________________________ 59 A.1- IMPORTANCE QUANTITATIVE DES PRIMATES PAR RAPPORT AUX AUTRES ANIMAUX___________________________________________________ 60 A.1.1- Cas de l’Amérique du Nord _______________________________________ 60 A.1.2- Cas de l’Europe ________________________________________________ 60 A.2- UTILISATION DES PRIMATES PAR SECTEUR DE RECHERCHE ________ 61 A.3- REPARTITION DES DIFFERENTES ESPECES DE PRIMATES ___________ 62 A.3.1- Cas de l’Amérique du Nord _______________________________________ 62 A.3.2- Cas de l’Europe ________________________________________________ 63 A.4- LES PRIMATES UTILISES POUR LA RECHERCHE SUR LE PALUDISME _ 63 B- LES PLASMODIUMS DES PRIMATES NON-HUMAINS _________________ 64 B.1- HISTORIQUE_____________________________________________________ 64 B.2- LES PLASMODIUMS ET LEURS HOTES NATURELS __________________ 66 B.3- CYCLE DU PLASMODIUM CHEZ LES PRIMATES_____________________ 67 B.4- CLINIQUE _______________________________________________________ 67 B.5- DIAGNOSTIC ____________________________________________________ 68 B.6- THERAPEUTIQUE ________________________________________________ 69 C- INTERETS DES PRIMATES AFRICAINS DANS LA RECHERCHE SUR LE PALUDISME___________________________________________________________ 69 C.1- INTERET EN TANT QUE MODELE ANIMAL _________________________ 69 C.1.1- Par rapport aux modèles bio-informatiques ___________________________ 70 C.1.2- Par rapport aux modèles in vitro ___________________________________ 70 C.1.3- Par rapport à une étude directe sur l’humain __________________________ 71 C.2- INTERET PAR RAPPORT AUX MODELES NON PRIMATES ____________ 72 C.2.1- Sensibilité croisée des plasmodiums ________________________________ 72 C.2.2- Proximité des tableaux cliniques ___________________________________ 76 C.2.3- Proximité des systèmes immunitaires _______________________________ 77 C.3- INTERET PAR RAPPORT AUX AUTRES PRIMATES ___________________ 78 C.3.1- Proximité phylogénétique des primates africains avec l’homme___________ 79 C.3.2- Sensibilité aux quatre plasmodiums humains _________________________ 81 C.3.3- Sensibilité aux infections par les sporozoïtes de P. falciparum __ 82 C.3.4- Forte reproductibilité des résultats __________________________________ 82 C.3.5- Sensibilité à d’autres plasmodiums simiens___________________________ 82 C.3.6- Proximité phylogénétique de leurs plasmodiums naturels avec P. falciparum 83 C.3.7- Disponibilité et facilité d’élevage __________________________________ 83 D- LIMITES D’UTILISATION DES PRIMATES AFRICAINS DANS LA RECHERCHE SUR LE PALUDISME______________________________________ 84 D.1- LIMITES BIOLOGIQUES___________________________________________ 84 D.1.1- Intérêt de l’utilisation des techniques in vitro _________________________ 84 D.1.2- Limites du modèle animal ________________________________________ 84 D.1.3- Avantages des autres modèles animaux par rapport aux primates
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