Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels

Brown, Alistair J. P.; Brown, Gordon D.; Netea, Mihai G.; Gow, Neil A. R.

doi:10.1016/j.tim.2014.07.001

Cited by 212 publications

(190 citation statements)

References 100 publications

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“…and generating precursors for energy required for the cell. Metabolism also contributes to virulence by enhancing stress adaptation (Brown et al 2014). For example, carbon adaptation is important for cell wall architecture.…”

Section: Discussionmentioning

confidence: 99%

“…Zcf15 and Zcf29 regulate carbon and nitrogen metabolism, respectively, two major nutritional requirements that contribute to pathogen fitness (Madhani and Fink 1998;Lorenz and Fink 2002;Brown et al 2014). Together they regulate iron metabolism, another key micronutrient required for pathogen fitness during infection.…”

Section: Discussionmentioning

confidence: 99%

“…In the ecological niche of a host, the ability of a pathogen to reproduce sooner, faster, or in higher numbers, increases its fitness capacity, enabling it to perhaps live longer, survive against antimicrobial therapies, or disseminate and infiltrate deeper tissues and organs (Brown et al 2014). As a commensalpathogen, C. albicans coevolves with its human host, where these traits likely arise due to mutations.…”

Section: Discussionmentioning

confidence: 99%

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Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

et al. 2017

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Almost all humans are colonized with Candida albicans. However, in immunocompromised individuals, this benign commensal organism becomes a serious, life-threatening pathogen. Here, we describe and analyze the regulatory networks that modulate innate responses in the host niches. We identified Zcf15 and Zcf29, two Zinc Cluster transcription Factors (ZCF) that are required for C. albicans virulence. Previous sequence analysis of clinical C. albicans isolates from immunocompromised patients indicates that both ZCF genes diverged during clonal evolution. Using in vivo animal models, ex vivo cell culture methods, and in vitro sensitivity assays, we demonstrate that knockout mutants of both ZCF15 and ZCF29 are hypersensitive to reactive oxygen species (ROS), suggesting they help neutralize the host-derived ROS produced by phagocytes, as well as establish a sustained infection in vivo. Transcriptomic analysis of mutants under resting conditions where cells were not experiencing oxidative stress revealed a large network that control macro and micronutrient homeostasis, which likely contributes to overall pathogen fitness in host niches. Under oxidative stress, both transcription factors regulate a separate set of genes involved in detoxification of ROS and down-regulating ribosome biogenesis. ChIP-seq analysis, which reveals vastly different binding partners for each transcription factor (TF) before and after oxidative stress, further confirms these results. Furthermore, the absence of a dominant binding motif likely facilitates their mobility, and supports the notion that they represent a recent expansion of the ZCF family in the pathogenic Candida species. Our analyses provide a framework for understanding new aspects of the interface between C. albicans and host defense response, and extends our understanding of how complex cell behaviors are linked to the evolution of TFs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

et al. 2017

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“…Cells exposed to ascorbate in PBS with shaking were killed at 37°C, whereas no killing was detected at 4°C. To date, C. albicans stress responses have mainly been investigated on cells cultured on rich, glucose-containing media and this environment differs significantly from mammalian host microenvironments that are often glucose limited [40]. To examine the effects of different media, ascorbate sensitivity was tested in YPD, YPG and PBS media.…”

Section: Discussionmentioning

confidence: 99%

“…Metabolism contributes to stress adaptation by generating antioxidants such as glutathione for which the cells need both carbon and nitrogen. Therefore both YPD and YPG could exert dramatic effects upon the stress resistance of C. albicans and protect against ascorbate [40,41]. Subsequently, when glucose as a carbon source was introduced into PBS in the absence of nitrogen, ascorbate k illing was p artially inhibited.…”

Section: Discussionmentioning

confidence: 99%

Sodium Ascorbate Kills Candida Albicans in Vitro Via Iron-Catalyzed Fenton Reaction: Importance of Oxygenation and Metabolism

et al. 2016

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aim: Ascorbate can inhibit growth and even decrease viability of various microbial species including Candida albicans. However the optimum conditions and the mechanism of action are unclear. Materials/methodology: Candida albicans shaken for 90 min in a buffered solution of ascorbate (90 mM) gave a 5-log reduction of cell viability, while there was no killing without shaking, in growth media with different carbon sources or at 4°C. Killing was inhibited by the iron chelator 2,2′-bipyridyl. Hydroxyphenyl fluorescein probe showed the intracellular generation of hydroxyl radicals. Results/conclusion: Ascorbate-mediated killing of C. albicans depends on oxygenation and metabolism, involves iron-catalyzed generation of hydroxyl radicals via Fenton reaction and depletion of intracellular NADH. Ascorbate could serve as a component of a topical antifungal therapy. Keywords• ascorbate • Candida albicans • hydroxyl radicals • oxidative stress • vitamin C Candida albicans is a major opportunistic fungal pathogen that is associated with a range of clinical conditions. The organism can lead to superficial infections of genital, oral and cutaneous sites as well as systemic infections, especially in hospitalized and/or immunocompromised patients, such as those suffering from AIDS or undergoing chemotherapy [1][2][3][4]. Although most superficial infections caused by C. albicans are not life threatening, these infections can have debilitating effects on the patient's quality of life. Several classes of antifungal agents (e.g., azoles, echinocandins) have been developed which are active against Candida infections; however, possible drug interactions and adverse side-effects, emergence of drug-resistant isolates, as well as the high costs of some of these agents underscore the necessity for development of additional treatment alternatives [3,5].Ascorbate (vitamin C, ascorbic acid) is an essential vitamin and is considered to be a potent antioxidant owing to its ability to act as an electron-donating reducing agent, and a quencher of reactive oxygen species (ROS) [6]. However, there is also increasing evidence that at pharmacologic concentrations, ascorbate can exert pro-oxidant effects via the reduction of transition metal ions, such as iron and copper [7]. Previous studies have shown that high-dose ascorbate exerts selective cytotoxic effects on cancer cells both in vitro and in vivo [6,8]. There have also been several clinical trials in cancer patients, testing the effects of high-dose ascorbate either alone or in For reprint orders, please contact: reprints@futuremedicine.com

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Candida , Cryptococcus , and Other Yeasts of Medical Importance

Borman,

Johnson

2023

ClinMicroNow

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Unicellular fungi which typically divide by budding have traditionally been referred to as yeasts. The rapidly expanding use of molecular identification strategies has permitted detailed phylogenetic analyses, allowing more accurate delineation of taxonomic boundaries and the reclassification of many yeast species and genera. Molecular identification approaches have also further added to the taxonomic complexity via the delineation of a number of cryptic species and species complexes in many traditional Candida species that can be separated only based on DNA sequencing analysis. The heterogeneous genus Candida belongs to the order Saccharomycetales within the ascomycetes. Rhodotorula spp. and species in the allied genus Cystobasidium share many similar physiologic and morphologic properties with Cryptococcus spp., as they are round to oval‐shaped, multilateral budding yeasts with capsules, although capsules, when present, are typically small. Carbohydrate antigens have provided useful targets for several commercial kits for the detection of disseminated candidiasis.

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Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels

Cited by 212 publications

References 100 publications

Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

Sodium Ascorbate Kills Candida Albicans in Vitro Via Iron-Catalyzed Fenton Reaction: Importance of Oxygenation and Metabolism

Candida , Cryptococcus , and Other Yeasts of Medical Importance

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