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RNA sequencing revealed novel actors of the acquisition of drug resistance in Candida albicans

ABSTRACT: Drug susceptible clinical isolates of Candida albicans frequently become highly tolerant to drugs during chemotherapy, with dreadful consequences on 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. RNA-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 sensitive 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. Our results open new perspectives to the role of Czf1 and to our understanding of the transcriptional and post-transcriptional mechanisms that lead to the acquisition of drug resistance in C. albicans, with potential future improvements of therapeutic strategies.

ORGANISM(S): Candida albicans

PROVIDER: GSE38298 | GEO | 2012/09/04

SECONDARY ACCESSION(S): PRJNA167631

REPOSITORIES: GEO

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Project description:Abstract: Candida parapsilosis and Candida albicans are human fungal pathogens that belong to the CUG clade in the Saccharomycotina. In contrast to C. albicans, relatively little is known about the virulence properties of C. parapsilosis, a pathogen particularly associated with infections of premature neonates. We describe here the construction of >200 C. parapsilosis strains carrying double allele deletions of transcription factors, protein kinases and species-specific genes. Two independent deletions were constructed for each target gene. Growth in > 40 conditions was tested, including carbon source, temperature, and the presence of antifungal drugs. The phenotypes were compared to C. albicans strains with deletions of orthologous transcription factors. We found that many phenotypes are shared between the two species, such as the role of Upc2 as a regulator of azole resistance. Others are unique. For example, Cph2 plays a role in the hypoxic response in C. parapsilosis and not in C. albicans. We found extensive divergence between the biofilm regulators of the two species. We identified 7 transcription factors and one protein kinase that are required for biofilm development in C. parapsilosis. Only three (Efg1, Bcr1, and Ace2) have similar effects on C. albicans biofilms, whereas Cph2, Czf1, Gzf3 and Ume6 have major roles in C. parapsilosis only. In addition, two transcription factors (Brg1 and Tec1) with well-characterized roles in biofilm formation in C. albicans do not have the same function in C. parapsilosis. We also compared the transcription profile of C. parapsilosis and C. albicans biofilms. Our analysis suggests the processes shared between the two species are predominantly metabolic. C. parapsilosis mRNA profiles of wild type (WT) at 37 degree celcius in planktonic growth conditions and ace2-/-, cph2-/-, efg1-/-, czf1-/-, ume6-/-, bcr1-/- and WT in biofilm conditions were generated by deep sequencing, in triplicate, using Illumina HiSeq2000.

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RNA sequencing revealed novel actors of the acquisition of drug resistance in Candida albicans

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