Laccase Protects<i>Cryptococcus neoformans</i>from Antifungal Activity of Alveolar Macrophages

Liu, Lide; Tewari, Ram P.; Williamson, Peter R.

doi:10.1128/iai.67.11.6034-6039.1999

Cited by 165 publications

(78 citation statements)

References 45 publications

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“…Laccase activity in C. neoformans is induced by Fe (Zhu and Williamson 2004). It is believed that cryptococcal laccase-iron oxidase activity may protect the fungus from macrophage infections by maintaining Fe in an oxidized form, thereby decreasing the production of antifungal hydroxyl radicals via Fenton reactions (Liu et al 1999). Most recently, the genome of Phanerochaete chrysosporium was searched for laccase-encoding sequences.…”

Section: Sample Culture Conditionsmentioning

confidence: 99%

Copper‐dependent iron transport in coastal and oceanic diatoms

Maldonado

Allen

Chong

et al. 2006

Limnology & Oceanography

211

229

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We investigated the presence of plasmalemma-bound copper-containing oxidases associated with the inducible iron (Fe) transport system in two diatoms of the genus Thalassiosira. Under Fe-limiting conditions, Thalassiosira oceanica, an oceanic isolate, was able to enzymatically oxidize inorganic Fe(II) extracellularly. This oxidase activity was dependent on copper (Cu) availability and diminished by exposure to a multi-Cu oxidase (MCO) inhibitor. The rates of Fe uptake from ferrioxamine B by Fe-limited T. oceanica were also dependent on Cu availability in the growth media. The effects of Cu limitation on Fe(II) oxidation and Fe uptake from ferrioxamine B were partially reversed after a short exposure to a Cu addition, indicating that the putative oxidases contain Cu. Limited physiological experiments were also performed with the coastal diatom Thalassiosira pseudonana and provided some evidence for putative Cu-containing oxidases in the high-affinity Fe transport system of this isolate. To support these preliminary physiological data, we searched the newly available T. pseudonana genome for a multi-Cu-containing oxidase gene and, using real-time polymerase chain reaction (PCR), quantified its expression under various Fe and Cu levels. We identified a putative MCO gene with predicted transmembrane domains and found that transcription levels of this gene were significantly elevated in Fe-limited cells relative to Fe-replete cells. These data collectively suggest that putative MCOs are part of the inducible Fe transport system of Fe-limited diatoms, which act to oxidize Fe(II) following reductive dissociation of Fe(III) from strong organic complexes.To date, most studies of Cu nutrition in marine phytoplankton have focused on its toxicity. Laboratory and field studies have shown that the concentrations of Cu(II) in some coastal regions are high enough to inhibit the growth of certain phytoplankton taxa (Brand et al. 1986) and to affect the composition of phytoplankton assemblages (Sunda et al. 1981;Moffett et al. 1997). In turn, phytoplankton are known to influence the speciation of dissolved Cu in seawater by releasing strong Cu organic ligands in response to Cu toxicity (Moffett and Brand 1996;Croot et al. 2000;Vasconcelos and Leal 2001).Less is known about the essentiality of Cu to marine phytoplankton. It has been established that Cu, a redoxactive transition metal, acts as a cofactor in enzymes that scavenge reactive oxygen species and catalyze other redox reactions, and is therefore vital for growth. Thus far, Cu has been shown to be involved in the detoxification of superoxide radicals (i.e., Cu-containing superoxide dismutases) (Chadd et al. 1996), the breakdown of organic N sources (Palenik et al. 1988(Palenik et al. , 1989, and the electron transport chain reactions of photosynthesis (i.e., plastocyanin) (Sandmann et al. 1983) and respiration (cytochrome oxidase) (Stryer 1988).One of the most intriguing findings about Cu nutrition in microorganisms over the past decade has been the identification of...

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Section: Sample Culture Conditionsmentioning

confidence: 99%

Copper‐dependent iron transport in coastal and oceanic diatoms

Maldonado

Allen

Chong

et al. 2006

Limnology & Oceanography

211

229

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“…For example, the presence of laccase has been shown to result in protection against murine alveolar macrophages without the addition of catecholamines, suggesting an intrinsic protective effect of laccase. In these studies, the finding of a novel iron oxidase activity of cryptococcal laccase as well as abolition of the laccase-protective effect by mannitol and accentuation by iron suggested that laccase may modulate macrophage-dependent Fenton reactions [39]. Another interesting laccase activity is the ability to produce oxygenated lipids from fatty acids [40].…”

Section: Roles Of Laccase-derived Products In the Virulence Of C Neomentioning

confidence: 99%

“…In the environment, induction of fungal laccases by iron has been proposed to modulate iron-catalyzed Fenton reactions during cellulose depolymerization [44]. In the mammalian host, iron within the phagolysosome may induce iron oxidase activity of laccase, which, in turn, reduces potentially toxic Fenton reactants [39]. Other regulatory stimuli are more difficult to understand in relationship to pathogenesis but provide key insights into the regulation of cryptococcal virulence.…”

Section: Molecular Regulation Of Laccase and Signal Transduction Pathmentioning

confidence: 99%

Role of laccase in the biology and virulence of

Zhu

Williamson

2004

FEMS Yeast Research

235

181

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Laccase is an important virulence factor for the human pathogen, Cryptococcus neoformans. In this review, we examine the structural, biological and genetic features of the enzyme and its role in the pathogenesis of cryptococcosis. Laccase is expressed in C. neoformans as a cell wall enzyme that possesses a broad spectrum of activity oxidizing both polyphenolic compounds and iron. Two paralogs, CNLAC1 and CNLAC2, are present in the fungus, of which the first one expresses the dominant enzyme activity under glucose starvation conditions. Regulation of the enzyme is in response to various environmental signals including nutrient starvation, the presence of multivalent cations and temperature stress, and is mediated through multiple signal transduction pathways. Study of the function and regulation of this important virulence factor has led to further understanding of mechanisms of fungal pathogenesis and the regulation of stress response in the host cell environment.

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“…One proposed mechanism of laccase-dependent virulence is that the enzyme oxidizes trace amounts of the neurotransmitter dopamine at the pathogen surface which then polymerizes to form melanin-like pigments (Nosanchuk et al ., 1998). Laccase may also have a direct immunoprotective function in the absence of dopamine by scavenging hydroxyl radicals produced by host macrophages by virtue of its Fe(II) oxidase activity (Liu et al ., 1999). Regardless of the mechanism of pathogenesis, expression of the laccase gene in vitro is strictly controlled by various growth conditions.…”

Section: Introductionmentioning

confidence: 99%

A CLC‐type chloride channel gene is required for laccase activity and virulence in Cryptococcus neoformans

Zhu

Williamson

2003

Molecular Microbiology

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SummaryLaccase is a major virulence factor required for infection caused by the human pathogenic yeast Cryptococcus neoformans . However, cellular processes involved in the regulation and expression of laccase remain largely unknown in C. neoformans . Here we report the identification of a chloride channel gene CLC-A which is essential for laccase activity in C. neoformans . CLC-A shares homology to CLC-type voltage-gated chloride channels from other organisms; for example, 63% homology to GEF1 , a chloride channel gene from Saccharomyces cerevisiae . A clca mutant, Mlac3, generated by insertional mutagenesis as well as a targeted D D D D clc-a mutant produced undetectable laccase in a liquid assay and produced no melanin on asparagine agar containing norepinephrine. Mlac3 was complemented with wild-type CLC-A which restored laccase activity and melanin biosynthesis. The clc-a mutants also showed reduced synthesis of another important virulence factor, capsule, and showed reduced growth at elevated pH. In addition, the clc-a mutation resulted in attenuated virulence in a mouse cryptococcosis model that was restored by complementation with wild-type CLC-A , indicating that the chloride channel plays an important role in the virulence of the organism. Further analysis revealed that the basis for absent laccase expression in the clc-a mutant was a laccase transcriptional defect that could be restored by adding exogenous copper. In conclusion, our findings show that CLC-A plays a role in the expression of two important virulence factors, capsule and laccase expression, which are required for virulence of the fungal pathogen.

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Laccase ProtectsCryptococcus neoformansfrom Antifungal Activity of Alveolar Macrophages

Cited by 165 publications

References 45 publications

Copper‐dependent iron transport in coastal and oceanic diatoms

Copper‐dependent iron transport in coastal and oceanic diatoms

Role of laccase in the biology and virulence of

A CLC‐type chloride channel gene is required for laccase activity and virulence in Cryptococcus neoformans

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