The bZip transcription factor Cgap1p is involved in multidrug resistance and required for activation of multidrug transporter gene CgFLR1 in Candida glabrata

Chen, Kuang Hua; Miyazaki, Taiga; Tsai, Huei Fung; Bennett, John E.

doi:10.1016/j.gene.2006.08.010

Cited by 89 publications

(94 citation statements)

References 46 publications

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“…Accordingly, an inactivation of these detoxifying enzymes leads to severe loss in virulence and viability inside immune cells (59). The oxidative stress response of C. glabrata is controlled by the transcription factors Yap1, Skn7, Msn2, and Msn4 (30,60,61), which mediate resistance of C. glabrata to H 2 O 2 and other oxidants. Additionally, C. glabrata possesses a catalase (Cta1p) that is required to survive oxidative stress (although this is dispensable in a mouse model of systemic infection) (60,62).…”

Section: Glabrata Cells Repress the Production Of High Ros Levelsmentioning

confidence: 99%

The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation

Seider

Brunke

Schild

et al. 2011

The Journal of Immunology

188

226

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Although Candida glabrata is an important human pathogenic yeast, its pathogenicity mechanisms are largely unknown. Immune evasion strategies seem to play key roles during infection, since very little inflammation is observed in mouse models. Furthermore, C. glabrata multiplies intracellularly after engulfment by macrophages. In this study, we sought to identify the strategies that enable C. glabrata to survive phagosome biogenesis and antimicrobial activities within human monocyte-derived macrophages. We show that, despite significant intracellular proliferation, macrophage damage or apoptosis was not apparent, and production of reactive oxygen species was inhibited. Additionally, with the exception of GM-CSF, levels of pro- and anti-inflammatory cytokines were only marginally increased. We demonstrate that adhesion to and internalization by macrophages occur within minutes, and recruitment of endosomal early endosomal Ag 1 and lysosomal-associated membrane protein 1 indicates phagosome maturation. However, phagosomes containing viable C. glabrata, but not heat-killed yeasts, failed to recruit cathepsin D and were only weakly acidified. This inhibition of acidification did not require fungal viability, but it had a heat-sensitive surface attribute. Therefore, C. glabrata modifies the phagosome into a nonacidified environment and multiplies until the host cells finally lyse and release the fungi. Our results suggest persistence of C. glabrata within macrophages as a possible immune evasion strategy.

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Section: Glabrata Cells Repress the Production Of High Ros Levelsmentioning

confidence: 99%

The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation

Seider

Brunke

Schild

et al. 2011

The Journal of Immunology

188

226

View full text Add to dashboard Cite

show abstract

“…Up-to-date research has highlighted the important role that complex resistance gene overexpression interactions play in FLC resistance in C. glabrata, and has demonstrated that overexpression of ABC membrane transporter genes is a pivotal FLC resistance mechanism in C. glabrata clinical isolates (Abbes et al, 2013). Although the MFS transporter genes FLR1 and QDR2 in C. glabrata are known to be involved in azole efflux, the expression of FLR1 and QDR2 in C. glabrata was not found to confer resistance to FLC (Chen et al, 2007;Costa et al, 2013). Therefore, the investigation of FLC resistance gene expression did not involve the MFS transporter genes in this work.…”

Section: Discussionmentioning

confidence: 94%

Resistance reversal induced by a combination of fluconazole and tacrolimus (FK506) in Candida glabrata

Chen

Zhang

Gao

et al. 2015

Journal of Medical Microbiology

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There is an increasing concern about Candida glabrata due to its high isolation frequency in candidiasis recently and notorious drug resistance to fluconazole. Drug combination is one effective approach to counteract drug resistance. This study aimed to test whether a combination of fluconazole and tacrolimus (FK506) had a synergistic effect on C. glabrata, and to seek the potential mechanisms underlying the synergistic effects. In vitro effects of fluconazole and FK506 against C. glabrata with different susceptibilities were investigated by a chequerboard method and a time-kill curve method. The mechanistic studies against the resistant C. glabrata were performed from two aspects: quantification of expression levels of fluconazole resistance genes (ERG11, CDR1, PDH1 and SNQ2) by real-time quantitative PCR and functional assays of drug efflux pumps. The addition of FK506 resulted in a decrease in the MIC of fluconazole from 32 to 8 mg ml "1 against the dose-dependent susceptible C. glabrata, and from 256 to 16 mg ml "1 against the resistant C. glabrata, respectively. The synergy was further confirmed by the time-kill assay. The expression levels of the ERG11 and SNQ2 genes were significantly downregulated after exposure to the drug combination, whereas that of the CDR1 gene was significantly upregulated, and no significant change in expression of PDH1 gene was observed. Flow cytometric assays showed that FK506 reduced the efflux of fluconazole. Tacrolimus enhanced the susceptibility of fluconazole against resistant C. glabrata by reducing the expression levels of the ERG11 and SNQ2 genes and inhibiting fluconazole efflux.

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“…They are respectively named Cgap1p and Cap1p and are also involved in the response to oxidative stress (Chen et al, 2007;Lelandais et al, 2008;Znaidi et al, 2009). Infections caused by fungal pathogens have become major life-threatening diseases, especially in patients with defects in their immune system.…”

Section: Yap Proteins and The Response To Oxidative Stressmentioning

confidence: 99%

“…In contrast to S. cerevisiae, in which an important number of functional information concerning Yap proteins is available (see (Rodrigues-Pousada et al, 2010) for review), very few studies have yet been carried out in Candida species to analyze the redundant Yap families (Chen et al, 2007;Singh et al, 2011). Most information is currently based on sequence similarity with Yap genes of S. cerevisiae.…”

Section: Characterisation Of the Yap Families In Candida Speciesmentioning

confidence: 99%

Role of the Yap Family in the Transcriptional Response to Oxidative Stress in Yeasts

Goudot¹,

Devaux²,

Lelandais³

2012

Oxidative Stress - Molecular Mechanisms and Biological Effects

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The bZip transcription factor Cgap1p is involved in multidrug resistance and required for activation of multidrug transporter gene CgFLR1 in Candida glabrata

Cited by 89 publications

References 46 publications

The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation

The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation

Resistance reversal induced by a combination of fluconazole and tacrolimus (FK506) in Candida glabrata

Role of the Yap Family in the Transcriptional Response to Oxidative Stress in Yeasts

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