Human β-Defensins Kill
            <i>Candida albicans</i>
            in an Energy-Dependent and Salt-Sensitive Manner without Causing Membrane Disruption

Vylkova, Slavena; Nayyar, Namrata; Li, Wansheng; Edgerton, Mira

doi:10.1128/aac.00478-06

Cited by 133 publications

(110 citation statements)

References 33 publications

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“…Taken together, therefore, the data suggest that caspofungin at concentrations below the MIC causes C. albicans cells to undergo apoptosis but that increasing caspofungin concentrations above the MIC does not further induce programmed cell death responses. Previous studies have shown that several stimuli, including acetic acid (7), hydrogen peroxide (27), 1,10-phenanthroline metal complexes (28), silver-coumarin complexes (17), diallyl disulfide (29), farsenol (26), lactoferrin (30), defensins (31), and the antifungal agent amphotericin B (9), cause C. albicans cells to undergo apoptosis. Our data demonstrate that cell wall stress stemming from inhibition of (1,3)-␤-D-glucan, as caused by caspofungin and Zymolyase (at concentrations Ն0.1 mg/ml), is also a trigger for apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Caspofungin Kills Candida albicans by Causing both Cellular Apoptosis and Necrosis

Hao

Cheng

Clancy

et al. 2013

Antimicrob Agents Chemother

152

132

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Caspofungin exerts candidacidal activity by inhibiting cell wall (1,3)-␤-D-glucan synthesis. We investigated the physiologic mechanisms of caspofungin-induced Candida albicans cell death. Apoptosis (programmed cell death) and necrosis were studied after C. albicans SC5314 cells were exposed to caspofungin at 0.06, 0.125, and 0.5 g/ml (0.5؋, 1؋, and 4؋ the MIC, respectively) for 3 h. Caspofungin at 0.125 and 0.5 g/ml reduced cellular viability by >50%, as measured by colony counts and methylene blue exclusion. Apoptosis and necrosis were demonstrated by annexin V and propidium iodide staining for phosphatidylserine externalization and loss of membrane integrity, respectively. At all concentrations of caspofungin, 20 to 25% and 5 to 7% of C. albicans cells exhibited early apoptosis and late apoptosis/necrosis, respectively (P value was not significant [NS]). Necrosis, on the other hand, was significantly greater at 0.125 (43%) and 0.5 (48%) g/ml than at 0.06 g/ml (26%) (P values of 0.003 and 0.003, respectively). The induction of apoptosis at concentrations less than or equal to the MIC was corroborated by dihydrorhodamine 123 (DHR-123) and dihydroethidium (DHE) staining (reactive oxygen species production), JC-1 staining (mitochondrial membrane potential dissipation), and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and 4=,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining (DNA damage and nuclear fragmentation). Moreover, electron microscopy of cells exposed to 0.125 g/ml of caspofungin showed hallmark apoptotic features like chromatin margination and condensation and nuclear blebs. Apoptosis was associated with metacaspase 1 activation, as demonstrated by D2R staining. Caspofungin exerts activity against C. albicans by directly killing cells (resulting in necrosis) and causing others to undergo programmed cell death (apoptosis). Apoptosis is initiated at subinhibitory concentrations, suggesting that strategies to target this process may augment the benefits of antifungal agents.C aspofungin and other agents in the echinocandin class of antifungals have assumed an increasingly important role in the therapy of invasive candidiasis (1). These agents are nontoxic and exert potent fungicidal activity against Candida albicans and other Candida spp. Their antifungal activity is achieved through inhibition of (1,3)-␤-D-glucan synthase (2), an enzyme that synthesizes a major constituent of the fungal cell wall. Although the mechanism of activity for the echinocandins is known, the physiological mechanisms by which they cause cell death are not defined. At least two types of mammalian cell death, necrosis and apoptosis, have been described (3). Necrosis is death resulting from direct cellular injury, which is best defined by cell and organelle swelling and lysis (4). Apoptosis, on the other hand, is programmed cell death, the principal morphological feature of which is shrinkage of the cell and its nucleus (3, 4).Over the last decade, there have been a number of reports on apoptosis in yeas...

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Section: Discussionmentioning

confidence: 99%

Caspofungin Kills Candida albicans by Causing both Cellular Apoptosis and Necrosis

Hao

Cheng

Clancy

et al. 2013

Antimicrob Agents Chemother

152

132

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“…They do not seem to cause gross membrane disruption in C. albicans (21), and a moderate membrane permeabilization has been reported only for hBD-3 (21,12).…”

mentioning

confidence: 99%

“…Human ␤-defensins 2 and 3 (hBD-2 and hBD-3) display potent in vitro activity against C. albicans (11,10,21), but their antifungal mechanism is poorly understood. They do not seem to cause gross membrane disruption in C. albicans (21), and a moderate membrane permeabilization has been reported only for hBD-3 (21,12).…”

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confidence: 99%

Interaction between the Candida albicans High-Osmolarity Glycerol (HOG) Pathway and the Response to Human β-Defensins 2 and 3

et al. 2011

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“…Salivary histatin 5 induces fungal cell death via the release of cellular ATP and activation of P2X receptors (13), in a process that involves an interaction with cell wall proteins (14) and a potassium channel (15). Human beta-defensins display some shared mechanisms with histatin 5, yet synergy between some beta-defensins and histatin 5 indicates that not all targets are shared (16). The human cathelicidin LL-37 acts via disruption of the plasma membrane.…”

mentioning

confidence: 99%

Identification and Mechanism of Action of the Plant Defensin NaD1 as a New Member of the Antifungal Drug Arsenal against Candida albicans

Hayes

Bleackley

Wiltshire

et al. 2013

Antimicrob Agents Chemother

110

165

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bIn recent decades, pathogenic fungi have become a serious threat to human health, leading to major efforts aimed at characterizing new agents for improved treatments. Promising in this context are antimicrobial peptides produced by animals and plants as part of innate immune systems. Here, we describe an antifungal defensin, NaD1, with activity against the major human pathogen Candida albicans, characterize the mechanism of killing, and identify protection strategies used by the fungus to survive defensin treatment. The mechanism involves interaction between NaD1 and the fungal cell surface followed by membrane permeabilization, entry into the cytoplasm, hyperproduction of reactive oxygen species, and killing induced by oxidative damage. By screening C. albicans mutant libraries, we identified that the high-osmolarity glycerol (HOG) pathway has a unique role in protection against NaD1, while several other stress-responsive pathways are dispensable. The involvement of the HOG pathway is consistent with induction of oxidative stress by NaD1. The HOG pathway has been reported to have a major role in protection of fungi against osmotic stress, but our data indicate that osmotic stress does not contribute significantly to the adverse effects of NaD1 on C. albicans. Our data, together with previous studies with human beta-defensins and salivary histatin 5, indicate that inhibition of the HOG pathway holds promise as a broad strategy for increasing the activity of antimicrobial peptides against C. albicans.

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Human β-Defensins Kill Candida albicans in an Energy-Dependent and Salt-Sensitive Manner without Causing Membrane Disruption

Cited by 133 publications

References 33 publications

Caspofungin Kills Candida albicans by Causing both Cellular Apoptosis and Necrosis

Caspofungin Kills Candida albicans by Causing both Cellular Apoptosis and Necrosis

Interaction between the Candida albicans High-Osmolarity Glycerol (HOG) Pathway and the Response to Human β-Defensins 2 and 3

Identification and Mechanism of Action of the Plant Defensin NaD1 as a New Member of the Antifungal Drug Arsenal against Candida albicans

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