Genomic polymorphism in the population of Candida glabrata: Gene copy-number variation and chromosomal translocations

Muller, Héloïse; Thierry, Agnès; Coppée, Jean‐Yves; Gouyette, Catherine; Hennequin, Christophe; Sismeiro, Odile; Talla, Emmanuel; Dujon, Bernard; Fairhead, Cécile

doi:10.1016/j.fgb.2008.11.006

Cited by 65 publications

(81 citation statements)

References 67 publications

(58 reference statements)

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“…Such a difference was not evident from probing the large, terminal EPA1-containing chromosome E fragment following PmeI or StuI digestion of C. glabrata genomic DNA and separation by field inversion gel electrophoresis (data not shown). Consistent with this, the total length of chromosome E is the same in BG2 and CBS138 (32).…”

Section: Expression Of Epa1 Is Heterogeneous and Is Related To Adheresupporting

confidence: 78%

“…A previous study assigned the differing responses to osmotic stress between these two C. glabrata strains to a sequence difference in a MAPKKK gene (19). Sequences in and around EPA1 are near identical in the two strains, including the number of repeats of the EPA1 120-bp minisatellite (13,32,46,52). The heterogeneity difference was retained when the same Epa1-HA construct was expressed in both strains.…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, the heterogeneity difference was retained when the same Epa1-HA construct was expressed in both strains. Genomic polymorphism involving translocations and re-combination between repeat sequences in the (sub)telomeric regions is widespread in C. glabrata (32,37,53). Any such events leading to an altered distance of the EPA1 locus from the chromosome end could explain the present strain difference: the strength of Sir-dependent silencing decreases with distance from telomeres (41,51).…”

Section: Expression Of Epa1 Is Heterogeneous and Is Related To Adherementioning

confidence: 90%

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Heterogeneous Expression of the Virulence-Related Adhesin Epa1 between Individual Cells and Strains of the Pathogen Candida glabrata

et al. 2012

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We investigated the relevance of gene expression heterogeneity to virulence properties of a major fungal pathogen, Candida glabrata. The organism's key virulence-associated factors include glycosylphosphatidylinositol-anchored adhesins, encoded subtelomerically by the EPA gene family. Individual-cell analyses of expression revealed very striking heterogeneity for Epa1, an adhesin that mediates ϳ95% of adherence to epithelial cells in vitro. The heterogeneity in Epa1 was markedly greater than that known for other yeast genes. Sorted cells expressing high or low levels of Epa1 exhibited high and low adherence to epithelial cells, indicating a link between gene expression noise and potential virulence. The phenotypes of sorted subpopulations reverted to mixed phenotypes within a few generations. Variation in single-cell Epa1 protein and mRNA levels was correlated, consistent with transcriptional regulation of heterogeneity. Sir-dependent transcriptional silencing was the primary mechanism driving heterogeneous Epa1 expression in C. glabrata BG2, but not in CBS138 (ATCC 2001). Inefficient silencing in the latter strain was not due to a difference in EPA1 sequence or (sub)telomere length and was overcome by ectopic SIR3 expression. Moreover, differences between strains in the silencing dependence of EPA1 expression were evident across a range of clinical isolates, with heterogeneity being the greatest in strains where EPA1 was subject to silencing. The study shows how heterogeneity can impact the virulence-related properties of C. glabrata cell populations, with potential implications for microbial pathogenesis more broadly.

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Section: Expression Of Epa1 Is Heterogeneous and Is Related To Adheresupporting

confidence: 78%

Section: Discussionmentioning

confidence: 97%

Section: Expression Of Epa1 Is Heterogeneous and Is Related To Adherementioning

confidence: 90%

See 1 more Smart Citation

Heterogeneous Expression of the Virulence-Related Adhesin Epa1 between Individual Cells and Strains of the Pathogen Candida glabrata

et al. 2012

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“…Candida glabrata is capable of genomic changes, including point mutations as well as changes in chromosome structure that may be mechanisms of adaptation to changing environments (31,32). These genomic changes may be a coping mechanism that allows it to rapidly become resistant to multiple drugs following limited exposure (13,17,(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Role of FKS Mutations in Candida glabrata: MIC Values, Echinocandin Resistance, and Multidrug Resistance

Pham

Iqbal

Bolden

et al. 2014

Antimicrob Agents Chemother

189

149

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Candida glabrata is the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment of C. glabrata disease due to the high rate of resistance to fluconazole. Recent case reports indicate that C. glabrata resistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates of C. glabrata collected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions of FKS1 and FKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 in FKS1 and 35 in FKS2. All of the isolates with an FKS mutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S. C. glabrata isolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S. C. glabrata isolates for echinocandin resistance is warranted. Candida species continue to be a leading cause of bloodstream infection in U.S. hospitals, especially in intensive care units (1, 2). Although the antifungal armamentarium is limited, there are good options for the treatment of Candida species, especially with the arrival of the newest antifungal agents, the echinocandins (3, 4). The echinocandins are intravenously administered agents with a favorable safety profile. As inhibitors of 1,3-␤-D glucan synthase in the cell wall, they have a mechanism of action different from that of the older azole antifungals, which act to disrupt ergosterol (cell membrane) synthesis. This alternate mechanism of action allows the echinocandins to be effective against Candida isolates that are azole resistant. Early studies of in vitro susceptibility showed resistance to echinocandins to be extremely low for all Candida species (5, 6).Candida glabrata has recently become the second-most-frequent cause of candidemia in the United States, surpassing C. parapsilosis and C. tropicalis (6-8). While the ultimate cause for this increase in the prevalence of C. glabrata is unknown, the increase might be related to C. glabrata's higher incidence of resistance to fluconazole in comparison to most other Candida species (6-9). Because of the increased probability of fluconazole resistance, echinocandins are recommended as first-line therapy against C. glabrata (4). Alarmingly, C. glabrata is the first species of Candida for which measurable resistance to echinocandins has been detected (6, 10). Case reports of echinocandin-resistant C. glabrata following echin...

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“…These aneuploids were seen to develop in response to azole antifungals, indicating that aneuploids arise because of antifungal treatment during the infection process and are retained through selection for the increased azole resistance that they confer. Chromosome polymorphisms and copy number variation have also been researched in other pathogenic yeasts, including C. glabrata (Muller et al 2009) and C. neoformans (Morrow and Fraser 2013).…”

Section: Population Genomicsmentioning

confidence: 99%

Evolutionary Perspectives on Human Fungal Pathogens

Taylor

2014

Cold Spring Harb Perspect Med

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Genomic polymorphism in the population of Candida glabrata: Gene copy-number variation and chromosomal translocations

Cited by 65 publications

References 67 publications

Heterogeneous Expression of the Virulence-Related Adhesin Epa1 between Individual Cells and Strains of the Pathogen Candida glabrata

Heterogeneous Expression of the Virulence-Related Adhesin Epa1 between Individual Cells and Strains of the Pathogen Candida glabrata

Role of FKS Mutations in Candida glabrata: MIC Values, Echinocandin Resistance, and Multidrug Resistance

Evolutionary Perspectives on Human Fungal Pathogens

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