Abstract
BackgroundDrug susceptible clinical isolates of Candida albicans frequently become highly tolerant to drugs during chemotherapy, with dreadful consequences to patient health. We used RNA sequencing (RNA-seq) to analyze the transcriptomes of a CDR (Candida Drug Resistance) strain and its isogenic drug sensitive counterpart.ResultsRNA-seq unveiled differential expression of 228 genes including a) genes previously identified as involved in CDR, b) genes not previously associated to the CDR phenotype, and c) novel transcripts whose function as a gene is uncharacterized. In particular, we show for the first time that CDR acquisition is correlated with an overexpression of the transcription factor encoding gene CZF1. CZF1 null mutants were susceptible to many drugs, independently of known multidrug resistance mechanisms. We show that CZF1 acts as a repressor of β-glucan synthesis, thus negatively regulating cell wall integrity. Finally, our RNA-seq data allowed us to identify a new transcribed region, upstream of the TAC1 gene, which encodes the major CDR transcriptional regulator.ConclusionOur results open new perspectives of the role of Czf1 and of our understanding of the transcriptional and post-transcriptional mechanisms that lead to the acquisition of drug resistance in C. albicans, with potential for future improvements of therapeutic strategies.
Highlights
Drug susceptible clinical isolates of Candida albicans frequently become highly tolerant to drugs during chemotherapy, with dreadful consequences to patient health
Transcriptional landscape of Gu4 and Gu5 strains In order to conduct a comparative analysis of the transcriptomes of CDR versus drug susceptible C. albicans cells, we performed high-throughput sequencing of cDNA made from poly(A) RNAs obtained from the Gu4 and Gu5 strains
CZF1 overexpression is commonly associated with CDR acquisition To check whether an upregulation of CZF1 is a general phenomenon among drug resistant clinical isolates, we examined the expression of CZF1 in six azole sensitive revealed that CZF1 was upregulated in two AR isolates of the CDR group and one of the MDR group (DSY290/ DSY292; DSY347/DSY289; Gu4/Gu5) (Figure 6, upper left)
Summary
Drug susceptible clinical isolates of Candida albicans frequently become highly tolerant to drugs during chemotherapy, with dreadful consequences to patient health. The yeast Candida albicans is the major cause of opportunistic fungal infections in humans. There are two main groups of mutations which cause azole resistance in Candida albicans. The first group directly targets ERG11, either in cis by creating ERG11 alleles which encode a protein variant insensitive to azoles [4], or in trans by increasing the expression of ERG11 through gain of function mutations in the UPC2 gene, which encode a is controlled mainly by the Tac transcription factor [14]. Most of the CDR resistant strains present a loss of heterozygocity and/or aneuploidy at the TAC1 locus, combined to gain of function mutations of TAC1 [15,16]. Chromatine immunoprecipitation and tac1Δ strain analyses identified the TAC1 regulon, which is composed of about ten genes mostly involved in membrane properties, including CDR1, CDR2, the phospholipid transferase gene PDR16, the putative flippase gene RTA3 or the putative sphingosine kinase gene LCB4 [18,19]
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