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

Argimón, Silvia; Fanning, Saranna; Blankenship, Jill R.; Mitchell, Aaron P.

doi:10.1128/ec.00133-10

Cited by 41 publications

(30 citation statements)

References 20 publications

(21 reference statements)

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“…In C. albicans specifically, this pathway is activated by a range of stresses, including osmotic and oxidative stress (41,42). Importantly for our study, the Hog1 pathway is also activated after exposure of C. albicans to the antimicrobial peptides histatin 5 and human beta-defensins (43,47). Furthermore, the Hog1 pathway is also the only stress-responsive pathway implicated in the resistance of C. albicans to histatin 5 and human beta-defensins (43,47).…”

Section: Figmentioning

confidence: 60%

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

103

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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Section: Figmentioning

confidence: 60%

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

103

165

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“…Examples include the secretion of AMP-binding proteins that re- direct peptide antimicrobials away from microbial structures (52). As presented below, similar mechanisms were also shown for C. albicans (53)(54)(55)(56)(57)(58).…”

Section: Escape Strategies From Antimicrobial Peptidesmentioning

confidence: 74%

“…Physiological levels of Hst 5 activated the mitogen-activated protein kinase (MAPK) Hog1 (61) in wild-type cells, while hog1 mutants were hypersensitive to the AMP. Nonhuman AMPs (as discussed below) or human ␤-defensins were shown to trigger Hog1 activity by interaction with the upstream MAPK kinase Pbs2 to orchestrate a cell damage compensatory response (56,62). Accordingly, both hog1 and pbs2 mutants were supersensitive to treatment with the human ␤-defensins 2 and 3 (56).…”

Section: Escape Strategies From Antimicrobial Peptidesmentioning

confidence: 99%

“…Nonhuman AMPs (as discussed below) or human ␤-defensins were shown to trigger Hog1 activity by interaction with the upstream MAPK kinase Pbs2 to orchestrate a cell damage compensatory response (56,62). Accordingly, both hog1 and pbs2 mutants were supersensitive to treatment with the human ␤-defensins 2 and 3 (56). It has been reported that the high-osmolarity glycerol (HOG) pathway is involved in regulating ROS production and ATP demand by mitochondria (63).…”

Section: Escape Strategies From Antimicrobial Peptidesmentioning

confidence: 99%

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Interplay between Candida albicans and the Antimicrobial Peptide Armory

2014

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Antimicrobial peptides (AMPs) are key elements of innate immunity, which can directly kill multiple bacterial, viral, and fungal pathogens. The medically important fungus Candida albicans colonizes different host niches as part of the normal human microbiota. Proliferation of C. albicans is regulated through a complex balance of host immune defense mechanisms and fungal responses. Expression of AMPs against pathogenic fungi is differentially regulated and initiated by interactions of a variety of fungal pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on human cells. Inflammatory signaling and other environmental stimuli are also essential to control fungal proliferation and to prevent parasitism. To persist in the host, C. albicans has developed a three-phase AMP evasion strategy, including secretion of peptide effectors, AMP efflux pumps, and regulation of signaling pathways. These mechanisms prevent C. albicans from the antifungal activity of the major AMP classes, including cathelicidins, histatins, and defensins leading to a basal resistance. This minireview summarizes human AMP attack and C. albicans resistance mechanisms and current developments in the use of AMPs as antifungal agents.

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“…In addition, stress response pathways within the fungus are important for resistance to antimicrobial peptides. For example, an intact Hog1 mitogen-activated protein kinase pathway is required for resistance to multiple antimicrobial peptides (4,5). Previously, we determined that the regulatory factor Ssd1 plays a key role in antimicrobial peptide resistance in C. albicans (6).…”

mentioning

confidence: 99%

Bcr1 Functions Downstream of Ssd1 To Mediate Antimicrobial Peptide Resistance in Candida albicans

et al. 2013

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e In order to colonize the host and cause disease, Candida albicans must avoid being killed by host defense peptides. Previously, we determined that the regulatory protein Ssd1 governs antimicrobial peptide resistance in C. albicans. Here, we sought to identify additional genes whose products govern susceptibility to antimicrobial peptides. We discovered that a bcr1⌬/⌬ mutant, like the ssd1⌬/⌬ mutant, had increased susceptibility to the antimicrobial peptides, protamine, RP-1, and human ␤ defensin-2. Homozygous deletion of BCR1 in the ssd1⌬/⌬ mutant did not result in a further increase in antimicrobial peptide susceptibility. Exposure of the bcr1⌬/⌬ and ssd1⌬/⌬ mutants to RP-1 induced greater loss of mitochondrial membrane potential and increased plasma membrane permeability than with the control strains. Therefore, Bcr1 and Ssd1 govern antimicrobial peptide susceptibility and likely function in the same pathway. Furthermore, BCR1 mRNA expression was downregulated in the ssd1⌬/⌬ mutant, and the forced expression of BCR1 in the ssd1⌬/⌬ mutant partially restored antimicrobial peptide resistance. These results suggest that Bcr1 functions downstream of Ssd1. Interestingly, overexpression of 11 known Bcr1 target genes in the bcr1⌬/⌬ mutant failed to restore antimicrobial peptide resistance, suggesting that other Bcr1 target genes are likely responsible for antimicrobial peptide resistance. Collectively, these results demonstrate that Bcr1 functions downstream of Ssd1 to govern antimicrobial peptide resistance by maintaining mitochondrial energetics and reducing membrane permeabilization.T he fungus Candida albicans colonizes the skin and mucosal surfaces of healthy individuals, and colonization is necessary for the organism to cause both superficial and invasive disease. In order to successfully colonize the host and cause disease, C. albicans must resist killing by antimicrobial peptides produced by epithelial cells, leukocytes and platelets. In humans, these antimicrobial peptides include defensins, histatins, cathelicidins, kinocidins, and lactoferrin and transferrin family peptides (1).Several mechanisms that enable C. albicans to resist the injurious effects of antimicrobial peptides have been identified. These mechanisms include inactivation of antimicrobial peptides via either cleavage by secreted aspartyl proteases (2) or binding by secreted fragments of Msb2 (3). In addition, stress response pathways within the fungus are important for resistance to antimicrobial peptides. For example, an intact Hog1 mitogen-activated protein kinase pathway is required for resistance to multiple antimicrobial peptides (4, 5). Previously, we determined that the regulatory factor Ssd1 plays a key role in antimicrobial peptide resistance in C. albicans (6). A strain in which SSD1 was deleted was hypersusceptible to certain antimicrobial peptides, whereas strains that overexpressed SSD1 were resistant to these peptides. In addition, in a murine model of disseminated candidiasis, an ssd1⌬/⌬ null mutant had attenuated virulence, s...

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

Cited by 41 publications

References 20 publications

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

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

Interplay between Candida albicans and the Antimicrobial Peptide Armory

Bcr1 Functions Downstream of Ssd1 To Mediate Antimicrobial Peptide Resistance in Candida albicans

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