Differential Virulence of Candida glabrata Glycosylation Mutants

West, Lara J.; Lowman, Douglas W.; Mora-Montes, Héctor M.; Grubb, Sarah; Murdoch, Craig; Thornhill, Martin H.; Gow, Neil A. R.; Williams, David L.; Haynes, Ken

doi:10.1074/jbc.m113.478743

Cited by 55 publications

(79 citation statements)

References 86 publications

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“…This suggests that glucan exposure and DC phagocytic uptake are not necessarily correlated with cell wall glucan abundance and led to the hypothesis that the molecular structure of mannan may be the major determinant of glucan exposure. Consistent with this hypothesis, previous studies reported the molecular weight of C. albicans N-mannans to be 2.6-fold greater than that of C. glabrata (Hall et al, 2013; West et al, 2013). In addition, the molecular structure of C. glabrata mannan is lower in structural complexity relative to C. albicans (Shibata et al, 2012).…”

Section: Resultssupporting

confidence: 62%

“…To study how N-mannan structure affects glucan exposure in the relatively small mannans of C. glabrata, mannosylation mutants from West et al (2013) were utilized. The authors demonstrated alterations in mannan structure of Cg anp1 Δ, Cg mnn11Δ , and Cg mnn2Δ relative to the parental strain, ATCC2001.…”

Section: Resultsmentioning

confidence: 99%

“…The authors demonstrated alterations in mannan structure of Cg anp1 Δ, Cg mnn11Δ , and Cg mnn2Δ relative to the parental strain, ATCC2001. N-mannans in the mannosylation mutants are smaller than that of the parental strain, with Cg mnn2Δ mannan having the largest decrease in molecular weight (West et al, 2013) (Figure 1J). Both Cganp1Δ and Cgmnn11Δ strains have a reduced length of the mannan a-(1,6)mannose backbone but retain the a-(1,2) and a-(1,3)-mannose side chains in reduced abundance because of the shorter backbone (Figure 1H).…”

Section: Resultsmentioning

confidence: 99%

“…Serotype A C. albicans may also possess side chain β-(1,2) or (1,3) linked oligomannosides. Additionally, acid-labile β-mannoside moieties of variable length may be appended to N-mannan side chains via phosphodiester linkages (Cutler, 2001; Hall and Gow, 2013; Hall et al, 2013; West et al, 2013). β-(1,2)- or (1,3)-linked oligomannosides have also been identified in C. albicans as part of the phospholipomannan moiety of the cell wall (Trinel et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Mannan Molecular Substructures Control Nanoscale Glucan Exposure in Candida

et al. 2018

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SUMMARY Cell wall mannans of Candida albicans mask β-(1,3)-glucan from recognition by Dectin-1, contributing to innate immune evasion. Glucan exposures are predominantly single receptor-ligand interaction sites of nanoscale dimensions. Candida species vary in basal glucan exposure and molecular complexity of mannans. We used super-resolution fluorescence imaging and a series of protein mannosylation mutants in C. albicans and C. glabrata to investigate the role of specific N-mannan features in regulating the nanoscale geometry of glucan exposure. Decreasing acid labile mannan abundance and α-(1,6)-mannan backbone length correlated most strongly with increased density and nanoscopic size of glucan exposures in C. albicans and C. glabrata, respectively. Additionally, a C. albicans clinical isolate with high glucan exposure produced similarly perturbed N-mannan structures and elevated glucan exposure geometry. Thus, acid labile mannan structure influences the nanoscale features of glucan exposure, impacting the nature of the pathogenic surface that triggers immunoreceptor engagement, aggregation, and signaling.

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Section: Resultssupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mannan Molecular Substructures Control Nanoscale Glucan Exposure in Candida

et al. 2018

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“…The isolation frequency of C. glabrata among fungal isolates has risen significantly, accounting for 15-20 % of all Candida infections (Kauffman et al, 2000;Ruan & Hsueh, 2009;Rodrigues et al, 2014). C. glabrata is also a major cause of life-threatening disease in immunocompromised patients, causing up to 30 % of all candidaemias (West et al, 2013). Although the ratio of isolated C. glabrata species in candidiasis is lower than that for C. albicans, C. glabrata intrinsically possesses a higher resistance to fluconazole (FLC).…”

Section: Introductionmentioning

confidence: 99%

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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Candida glabrata: a deadly companion?

Bolotin‐Fukuhara

Fairhead

2014

Yeast

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The yeast Candida glabrata has become a major fungal opportunistic pathogen of humans since the 1980s. Contrary to what its name suggests, it is much closer, phylogenetically, to the model yeast Saccharomyces cerevisiae than to the most prevalent human fungal pathogen, Candida albicans. Its similarity to S. cerevisiae fortunately extends to their amenability to molecular genetics methods. C. glabrata is now described as part of the Nakaseomyces clade, which includes two new pathogens and other environmental species. C. glabrata is likely a commensal species of the human digestive tract, but systemic infections of immunocompromised patients are often fatal. In addition to being the subject of active medical research, other studies on C. glabrata focus on fundamental aspects of evolution of yeast genomes and adaptation. For example, the genome of C. glabrata has undergone major gene and intron loss compared to S. cerevisiae. It is also an apparently asexual species, a feature that inevitably leads to questions about the species' evolutionary past, present and future. On-going research with this yeast continues to address various aspects of adaptation to the human host and mechanisms of evolution in the Saccharomycetaceae, major model organisms for biology.

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Differential Virulence of Candida glabrata Glycosylation Mutants

Cited by 55 publications

References 86 publications

Mannan Molecular Substructures Control Nanoscale Glucan Exposure in Candida

Mannan Molecular Substructures Control Nanoscale Glucan Exposure in Candida

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

Candida glabrata: a deadly companion?

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