Regulation of the CgPdr1 Transcription Factor from the Pathogen Candida glabrata

Paul, Sanjoy; Schmidt, Jennifer A.; Moye‐Rowley, W. Scott

doi:10.1128/ec.00277-10

Cited by 69 publications

(106 citation statements)

References 41 publications

(59 reference statements)

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“…Azole resistance in this yeast species is mediated almost exclusively by upregulation of ABC transporters, including C. glabrata CDR1 (CgCDR1), C. glabrata PDH1 (CgPDH1), and C. glabrata SNQ2 (CgSNQ2) (30)(31)(32)(33)(34). C. glabrata possesses PDR1 as a transcriptional activator of these genes (35)(36)(37)(38). We have described a wide variety of GOF mutations in CgPDR1 (39).…”

mentioning

confidence: 99%

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Lohberger¹,

Coste²,

Sanglard³

2014

Eukaryot Cell

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Azoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur in Candida albicans principally by overexpression of multidrug transporter gene CDR1, CDR2, or MDR1 or by overexpression of ERG11, which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs) TAC1 (involved in the control of CDR1 and CDR2), MRR1 (involved in the control of MDR1), and UPC2 (involved in the control of ERG11). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial to C. albicans survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence of C. albicans in the absence of the selective drug pressure. In this work, the effect of GOF mutations on C. albicans virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neither TAC1 nor MRR1 GOF mutations had a significant effect on C. albicans virulence. In contrast, the presence of two hyperactive UPC2 alleles in C. albicans resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate with UPC2 hyperactive alleles was observed in competition experiments with the wild type in vivo but not in vitro. Interestingly, UPC2 hyperactivity delayed filamentation of C. albicans after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining the UPC2 GOF mutation with another hyperactive TF did not compensate for the negative effect of UPC2 on virulence. In conclusion, among the major TFs involved in azole resistance, only UPC2 had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.

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confidence: 99%

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Lohberger¹,

Coste²,

Sanglard³

2014

Eukaryot Cell

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“…Upregulation of ABC transporters occurs following alterations in their major regulator, the zinc cluster transcription factor CgPDR1 (10,11). CgPDR1 combines functional attributes of transcription factors PDR1 and PDR3 from the nonpathogenic baker's yeast Saccharomyces cerevisiae (12). We have previously found that gain-of-function (GOF) mutations in CgPDR1 lead not only to azole resistance in vitro and in vivo but also to gain of virulence in murine models of disseminated infection (13).…”

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confidence: 99%

Gain-of-Function Mutations in PDR1 , a Regulator of Antifungal Drug Resistance in Candida glabrata, Control Adherence to Host Cells

et al. 2013

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bCandida glabrata is an emerging opportunistic pathogen that is known to develop resistance to azole drugs due to increased drug efflux. The mechanism consists of CgPDR1-mediated upregulation of ATP-binding cassette transporters. A range of gainof-function (GOF) mutations in CgPDR1 have been found to lead not only to azole resistance but also to enhanced virulence. This implicates CgPDR1 in the regulation of the interaction of C. glabrata with the host. To identify specific CgPDR1-regulated steps of the host-pathogen interaction, we investigated in this work the interaction of selected CgPDR1 GOF mutants with murine bone marrow-derived macrophages and human acute monocytic leukemia cell line (THP-1)-derived macrophages, as well as different epithelial cell lines. GOF mutations in CgPDR1 did not influence survival and replication within macrophages following phagocytosis but led to decreased adherence to and uptake by macrophages. This may allow evasion from the host's innate cellular immune response. The interaction with epithelial cells revealed an opposite trend, suggesting that GOF mutations in CgPDR1 may favor epithelial colonization of the host by C. glabrata through increased adherence to epithelial cell layers. These data reveal that GOF mutations in CgPDR1 modulate the interaction with host cells in ways that may contribute to increased virulence.

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“…In C. glabrata, ABC-transporter regulation is more similar to that in S. cerevisiae (Paul et al 2011). Pleiotropic drug responsive elements (PDREs) present in CgCDR1, CgCDR2, and CgSNQ2 are structurally similar to those in S. cerevisiae (Sanglard et al 1999;Torelli et al 2008).…”

Section: Cis-acting Elementsmentioning

confidence: 99%

“…Pleiotropic drug responsive elements (PDREs) present in CgCDR1, CgCDR2, and CgSNQ2 are structurally similar to those in S. cerevisiae (Sanglard et al 1999;Torelli et al 2008). PDREs of CgCDR1 are necessary for high-level CDR1 expression in mitochondrial mutants (Paul et al 2011). …”

Section: Cis-acting Elementsmentioning

confidence: 99%

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Mechanisms of Antifungal Drug Resistance

Cowen

Sanglard

Howard

et al. 2014

Cold Spring Harb Perspect Med

479

399

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Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug-resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.

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Regulation of the CgPdr1 Transcription Factor from the Pathogen Candida glabrata

Cited by 69 publications

References 41 publications

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Gain-of-Function Mutations in PDR1 , a Regulator of Antifungal Drug Resistance in Candida glabrata, Control Adherence to Host Cells

Mechanisms of Antifungal Drug Resistance

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