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. PhD thesis Microbiologie appliquée, Microbiologie, INAPG 2006INAP0037 p.110.

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Abstract

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.

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