Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence.

Détails

Ressource 1Télécharger: journal.ppat.1000268.PDF (973.91 [Ko])
Etat: Serval
Version: Final published version
ID Serval
serval:BIB_8C6DE3D089DA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence.
Périodique
PLoS Pathogens
Auteur(s)
Ferrari S., Ischer F., Calabrese D., Posteraro B., Sanguinetti M., Fadda G., Rohde B., Bauser C., Bader O., Sanglard D.
ISSN
1553-7374[electronic]
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
5
Numéro
1
Pages
e1000268
Langue
anglais
Résumé
CgPdr1p is a Candida glabrata Zn(2)-Cys(6) transcription factor involved in the regulation of the ABC-transporter genes CgCDR1, CgCDR2, and CgSNQ2, which are mediators of azole resistance. Single-point mutations in CgPDR1 are known to increase the expression of at least CgCDR1 and CgCDR2 and thus to contribute to azole resistance of clinical isolates. In this study, we investigated the incidence of CgPDR1 mutations in a large collection of clinical isolates and tested their relevance, not only to azole resistance in vitro and in vivo, but also to virulence. The comparison of CgPDR1 alleles from azole-susceptible and azole-resistant matched isolates enabled the identification of 57 amino acid substitutions, each positioned in distinct CgPDR1 alleles. These substitutions, which could be grouped into three different "hot spots," were gain of function (GOF) mutations since they conferred hyperactivity to CgPdr1p revealed by constitutive high expression of ABC-transporter genes. Interestingly, the major transporters involved in azole resistance (CgCDR1, CgCDR2, and CgSNQ2) were not always coordinately expressed in presence of specific CgPDR1 GOF mutations, thus suggesting that these are rather trans-acting elements (GOF in CgPDR1) than cis-acting elements (promoters) that lead to azole resistance by upregulating specific combinations of ABC-transporter genes. Moreover, C. glabrata isolates complemented with CgPDR1 hyperactive alleles were not only more virulent in mice than those with wild type alleles, but they also gained fitness in the same animal model. The presence of CgPDR1 hyperactive alleles also contributed to fluconazole treatment failure in the mouse model. In conclusion, this study shows for the first time that CgPDR1 mutations are not only responsible for in vitro/in vivo azole resistance but that they can also confer a selective advantage under host conditions.
Mots-clé
ATP-Binding Cassette Transporters/genetics, Amino Acid Substitution, Animals, Candida glabrata/genetics, Candida glabrata/pathogenicity, Candidiasis/genetics, Candidiasis/microbiology, Drug Resistance, Fungal/genetics, Female, Fluconazole/pharmacology, Gene Expression Regulation, Fungal, Humans, Mice, Mice, Inbred BALB C, Mutation, Transcription Factors/genetics, Virulence/drug effects, Virulence/genetics
Pubmed
Web of science
Création de la notice
12/03/2009 19:06
Dernière modification de la notice
03/03/2018 19:13
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