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Gigou-cornet, Murielle (2006) Rôle des gènes RIM et VPS dans la signalisation du pH, la virulence et la résistance aux antifongiques chez la levure Candida albicans. Doctorat Microbiologie appliquée, Microbiologie, INAPG 2006INAP0037 p.110.
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Résumé
Candida albicans est le premier pathogène fongique de l’homme. Cette levure,
habituellement commensale, peut être à l’origine d’infections profondes mettant en jeu le
pronostic vital. L’incidence des candidoses profondes ne cesse d’augmenter parallèlement à
l’augmentation du nombre de patients à risque. La virulence de C. albicans s’explique par sa
capacité à coloniser puis envahir de nombreux tissus de l’organisme qui constituent autant de
microenvironnements différents. Les réponses adaptatives de la cellule aux modifications
environnementales sont déterminantes pour sa survie et conditionnent sa virulence. La voie
d’endocytose assure la dégradation ou le recyclage des protéines membranaires et joue un rôle
important dans la régulation des récepteurs. Elle est également impliquée dans l’activation de
la voie de signalisation du pH : la voie Rim.
Au début de ce travail, nous avons montré que la voie d’endocytose jouait un rôle
majeur dans la réponse au pH, la morphogenèse et la virulence de C. albicans, de façon à la
fois dépendante et indépendante de la voie Rim. Nous avons montré que les délétions de deux
gènes de la voie d’endocytose, VPS28 et VPS32, produisent non seulement les mêmes effets
que les délétions des gènes de la voie Rim, mais les aggravent.
Nous avons également mis en évidence le rôle de la voie Rim et des protéines Vps
dans la structure de la paroi et la résistance aux antifongiques azolés et aux échinocandines.
Là encore, la voie d’endocytose semble impliquée par son action spécifique dans la voie Rim
mais aussi par d’autres mécanismes indépendants de la voie Rim.
Enfin, nous avons caractérisé les mutants Carim9 et Carim21 et montré que les
protéines Rim9p et Rim21p sont toutes les deux indispensables à l’activation de la voie Rim
chez C. albicans. Ce résultat confirme que le mode d’activation de la voie Rim chez C.
albicans est proche de celui décrit chez S. cerevisiae et diffère sensiblement de celui
d’Aspergillus nidulans ou de Yarrowia lipolytica.
Nous avons montré que l’inhibition de la voie d’endocytose induit chez C. albicans
une réduction majeure de la virulence associée à une augmentation de la sensibilité aux
antifongiques azolés et aux échinocandines. En permettant la potentialisation de l’efficacité
des molécules existantes cette voie pourrait constituer une cible intéressante pour le
développement de nouveaux traitements antifongiques.
| Type d'EPrint: | Thèse (Doctorat) |
|---|---|
| Directeur de Mémoire: | Gaillardin, Claude |
| Date: | 21 Décembre 2006 |
| Jury de Mémoire: | Gaillardin, Claude et Bretagne,, Stéphane et Sanglard, Dominique et Dromer,, Françoise et Lavie-Richard, Mathias , |
| Ecole Doctorale: | ED 435 AGRICULTURE, ALIMENTATION, BIOLOGIE, ENVIRONNEMENTS ET SANTE |
| Discipline: | Microbiologie appliquée |
| Fonds: | INAPG |
| Institution: | INAPG |
| Laboratoire: | Microbiologie |
| Sujets: | 7. Sciences de la vie et ingénierie du vivant |
| Mots-clés libres: | Candida albicans, Antifongiques |
| Code ID: | 3116 |
| Déposé par : | Nadine Pontal |
| Déposé le : | 20 Novembre 2007 |
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