contribution of cgpdr1-regulated genes in enhanced virulence of azole-resistant candida glabrata的贡献azole-resistant念珠菌glabrata cgpdr1-regulated基因增强毒性.pdfVIP

Contribution of CgPDR1-Regulated Genes in Enhanced Virulence of Azole-Resistant Candida glabrata ´ ` 1 2 2 2 1 Selene Ferrari , Maurizio Sanguinetti , Riccardo Torelli , Brunella Posteraro , Dominique Sanglard * ` 1 Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland, 2 Institute of Microbiology, Universita Cattolica del Sacro Cuore, Rome, Italy Abstract In Candida glabrata, the transcription factor CgPdr1 is involved in resistance to azole antifungals via upregulation of ATP binding cassette (ABC)-transporter genes including at least CgCDR1, CgCDR2 and CgSNQ2. A high diversity of GOF (gain-of- function) mutations in CgPDR1 exists for the upregulation of ABC-transporters. These mutations enhance C. glabrata virulence in animal models, thus indicating that CgPDR1 might regulate the expression of yet unidentified virulence factors. We hypothesized that CgPdr1-dependent virulence factor(s) should be commonly regulated by all GOF mutations in CgPDR1. As deduced from transcript profiling with microarrays, a high number of genes (up to 385) were differentially regulated by a selected number (7) of GOF mutations expressed in the same genetic background. Surprisingly, the transcriptional profiles resulting from expression of GOF mutations showed minimal overlap in co-regulated genes. Only two genes, CgCDR1 and PUP1 (for PDR1 upregulated and encoding a mitochondrial protein), were commonly upregulated by all tested GOFs. While both genes mediated azole resistanc