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Role of Rim101p in the Ph Response in Candida Albicans Michael Weyler

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Role of Rim101p in the Ph Response in Candida Albicans Michael Weyler Role of Rim101p in the pH response in Candida albicans Michael Weyler To cite this version: Michael Weyler. Role of Rim101p in the pH response in Candida albicans. Biomolecules [q-bio.BM]. Université Paris Sud - Paris XI, 2007. English. tel-00165802 HAL Id: tel-00165802 https://tel.archives-ouvertes.fr/tel-00165802 Submitted on 27 Jul 2007 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE PARISXI UFR SCIENTIFIQUE D’ORSAY THESE présentée par Michael Weyler pour obtenir le grade de DOCTEUR EN SCIENCES DE L’UNIVERSITE PARISXI-ORSAY LE RÔLE DE RIM101p DANS LA RÉPONSE AU pH CHEZ CANDIDA ALBICANS Soutenance prévue le 6 juillet 2007 devant le jury composé de: Pr. Dr. H. Delacroix Président Dr. J-M. Camadro Rapporteur Pr. Dr. F. M. Klis Rapporteur Dr. G. Janbon Examinateur Dr. M. Lavie-Richard Examinateur Pr. Dr. C. Gaillardin Examinateur Remerciements Tout d’abord je voudrais remercier vivement mon directeur de thèse, Prof. Claude Gaillardin, pour m’avoir permis d’effectuer ce travail au sein de son laboratoire, pour ses conseils et sa disponibilité malgré son calendrier bien remplis. Je lui remercie également pour m’avoir laissé beaucoup de liberté dans mon travail, et pour la possibilité de participer aux différents congrès au cours de ma formation de thèse. Ensuite je tiens à remercier tous les autres membres du jury : à Dr Jean-Michel Camadro et Prof. Frans Klis d’avoir accepté d’être rapporteurs de cette thèse, à Prof. Hervé Delacroix pour la présidence, et à Dr. Guilhem Janbon et Dr. Mathias Lavie-Richard d’y participer en tant qu’examinateurs. A part Claude, j’y voudrais particulièrement mentionner deux personnes, qui m’ont soutenu tout au long de mon parcours de thésard : Frans en étant mon tuteur au sein du réseau européen « Galar FungailII » a qui j’ai toujours pu m’adresser pour des conseils indépendants, et Mathias, qui était pour moi la première adresse pour les grands et petits problèmes de toute sorte, en commençant par l’encadrement de mon travail pratique au labo, en passant par les problèmes administratives et en allant jusqu’à la correction orthographique de ma thèse. Un grand merci également à Grégory et Frédérique qui ont débuté ce travail avant mon arrivée au laboratoire et qui m’ont permis de prendre le relais sans faire tomber le bâton. Je remercie toute l’équipe de « Signalisation et Virulence » pour l’accueil chaleureuse et leur sincérité qui m’ont permis de vite trouver ma place dans ce groupe malgré mes difficultés avec la langue française. A ce propos, je voudrais également remercier Marie-Thérèse pour l’organisation de mes courses de français, et bien sûr Elisabeth et Colette pour l’enseignement. Sans eux, je crains que ces lignes soient complètement incompréhensibles. Je remercie aussi les membres du secrétariat, en particulier Caroline, Michèle et Anne pour l’aide avec toutes les démarches administratives qui étaient nécessaires tout au long de mon séjour au laboratoire. Ensuite je tiens à remercier tout les autres membres du laboratoire de Microbiologie et génétique moléculaire de Grignon qui ont rendus mon séjour ici très agréable. Au delà du labo, j’avais la chance de trouver des amis et des bons conseilleurs au sein du réseau européenne de recherche « Galar FungailII ». J’ai beaucoup profité des multiples formations et rencontres organisé par les différents équipes, et je ressens beaucoup de gratitude envers tout ses participants. Avant et à la fin de mon séjour à Grignon j’ai effectué quelques manips dans le laboratoire de Domenico Libri à Gif-sur-Yvette. Je tiens à remercier Domenico et toute son équipe pour l’accueil gentille qu’ils m’ont accordé à ces deux reprises, et pour leur aide dans des périodes critiques. Finalement je voudrais dire un grand merci à ma famille, à mes parents et mes sœurs qui m’ont soutenu à longe distance, et surtout à mon épouse Raquel, pour son soutien dans la vie quotidienne tout au long de ma thèse et sa patience avec moi notamment dans cette dernière période stressante de la rédaction. Résumé Candida albicans est une levure pathogène opportuniste qui appartient à la classe phylogénétique des hémiascomycetes comme environ 200 autres espèces du genre « Candida ». Seules quelques-unes d’entre elles sont considérées comme pathogènes et encore un plus petit nombre encore est fréquemment retrouvé dans les isolats cliniques (C. albicans , C. dubliniensis , C. parapsilosis , C. krusei , C. glabrata ) (Dujon 2006; Odds, Brown et al. 2006). C. albicans fait partie de la flore orale et intestinale normale d’environ 50-60% des êtres humains sans pour autant déclencher des infections. Cette levure est donc d’une part un composant normal de notre flore microbienne commensale de différentes zones du corps humain, dont la peau, la bouche, le vagin et le tractus gastro-intestinal. Elle est d’autre part le plus important pathogène fongique chez l’homme et peut dans certains cas causer des maladies diverses. Les infections diverses qui sont causé par C. albicans peuvent être classées en infections superficielles et en infections systémiques. Les infections superficielles, entraînant des lésions de la peau ou de la muqueuse orale ou vaginale, sont très communes, relativement faciles à diagnostiquer et sans danger pour la vie. Par contre, les infections systémiques sont plutôt rares, mais particulièrement dangereuses, et sont responsables d’une mortalité qui s’élève à environ 30 % chez les patients infectés. Une infection systémique passe généralement par plusieurs étapes. C. albicans doit d’abord traverser les barrières épithéliales, en franchissant la muqueuse intestinale par exemple. Dans tous les cas, les cellules de C. albicans s’attachent d’abord à un épithélium. Ensuite, elles peuvent pénétrer dans les tissus, gagner la voie sanguine et finalement disséminer dans tout l’organisme. Cette étape est facilitée pour les C. albicans qui peuvent coloniser un cathéter : ceux-ci constituent un facteur de risque majeur pour les candidoses disséminées. Après traversée des tuniques vasculaires, C. albicans va gagner accès à différents organes comme le rein ou le foie qu’elle colonisera. Des multiples facteurs peuvent déclencher une infection avec C. albicans , mais une condition générale pour sa pathogenèse est que le patient possède un système immunitaire affaibli. En général le système immunitaire est capable d’empêcher C. albicans d’envahir les tissus ; néanmoins de simples déséquilibres hormonaux, du pH ou de la flore microbienne peuvent provoquer des infections bénignes (Singh 2001; Macphail, Taylor et al. 2002). Les infections avec C. albicans peuvent devenir particulièrement dangereuses lorsque le système immunitaire humain est affaibli ou immature, comme par exemple dans le cas des patients atteints du SIDA, des nouveaux-nés, des patients en service de réanimation ou immunodéprimés suite à une transplantation d’organes ou une chimiothérapie (Wey, Mori et al. 1989; Bustamante 2005). C’est aussi pour cette raison que C. albicans est devenu un organisme modèle pour la recherche médicale. Le génome de C. albicans a été le premier génome d’un champignon pathogène qui ait été entièrement séquencé (Jones, Federspiel et al. 2004). L’un des principaux objectifs de la recherche sur C. albicans est de comprendre les mécanismes moléculaires de sa pathogenèse. Des nombreux gènes ont déjà été identifiés comme nécessaires dans divers modèles animaux d’infections (Navarro-Garcia, Sanchez et al. 2001; Gow, Brown et al. 2002), et de multiples facteurs de transcription semblent être impliqués dans la régulation de la transcription de ces gènes. Par conséquent, le réseau contrôlant l’expression du pouvoir pathogène est très complexe (Ernst 2000; Liu 2001). C. albicans est classé comme une levure, c'est-à-dire un champignon unicellulaire. Mais dans certaines conditions, d’autres phénotypes sont prédominants comme des les formes pseudohyphes ou vrais hyphes. La capacité d’alterner entre ces différents phénotypes est aujourd’hui considérée comme essentielle pour la pathogenèse : plusieurs travaux ont démontré que la plasticité morphologique est indispensable à la virulence de C. albicans (Odds, F. C., A. J. Brown, et al. 2006). La régulation de la transition entre la forme “levure” et la forme “hyphe” a donc intéressé la recherche depuis longtemps. L’une des raisons pour lesquelles les chercheurs s’intéressent à la réponse au pH de C. albicans concerne justement le rôle du pH dans cette transition morphologique. D’ailleurs, C. albicans est capable de pousser à des pH très différents, entre pH 2 et pH 10, et on peut imaginer que cette capacité à s’adapter au pH des différentes zones du corps humain peut être cruciale pour le succès de C. albicans comme commensal ou pathogène. Rim101p est connu comme un régulateur majeur de la réponse au pH ambiant, et sa présence est nécessaire pour la transition morphologique pH-dépendante ainsi que pour la croissance à des pH très élevés. Il a été démontré qu’une souche délétée pour RIM101 présente une virulence clairement diminuée dans un modèle de souris (Davis, Edwards et al. 2000), et que l’expression de plusieurs gènes connus pour être des cibles de Rim101p est nécessaire pour la pathogenèse dans des modèles animaux d’infections (Ghannoum, Spellberg et al. 1995) (De Bernardis, Muhlschlegel et al. 1998) (Soloviev, Fonzi et al. 2007). De plus, Rim101p est indispensable pour la formation des hyphes à pH alcalin (Davis, D.
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