Abstract
BackgroundCandida albicans is an opportunistic pathogen which is responsible for widespread nosocomial infections. It encompasses a fungus specific serine/threonine protein phosphatase gene, CaPPZ1 that is involved in cation transport, cell wall integrity, oxidative stress response, morphological transition, and virulence according to the phenotypes of the cappz1 deletion mutant.ResultsWe demonstrated that a short-term treatment with a sublethal concentration of tert-butyl hydroperoxide suppressed the growth of the fungal cells without affecting their viability, both in the cappz1 mutant and in the genetically matching QMY23 control strains. To reveal the gene expression changes behind the above observations we carried out a global transcriptome analysis. We used a pilot DNA microarray hybridization together with extensive RNA sequencing, and confirmed our results by quantitative RT-PCR. Novel functions of the CaPpz1 enzyme and oxidative stress mechanisms have been unraveled. The numbers of genes affected as well as the amplitudes of the transcript level changes indicated that the deletion of the phosphatase sensitized the response of C. albicans to oxidative stress conditions in important physiological functions like membrane transport, cell surface interactions, oxidation-reduction processes, translation and RNA metabolism.ConclusionsWe conclude that in the wild type C. albicans CaPPZ1 has a protective role against oxidative damage. We suggest that the specific inhibition of this phosphatase combined with mild oxidative treatment could be a feasible approach to topical antifungal therapy.
Highlights
Candida albicans is an opportunistic pathogen which is responsible for widespread nosocomial infections
A putative antifungal target In our previous publication [8] we proposed that a specific signal transduction regulator, the C. albicans protein phosphatase Z1 (CaPpz1) enzyme would be a suitable drug target for the following reasons: (i) The PPZ type phosphatases are restricted to fungal species [9]. (ii) CaPpz1 has important functions as it is involved in monovalent cation homeostasis, cell wall integrity and the pathogenicity of C. albicans [10, 11]. (iii) The deletion of Candida albicans protein phosphatase Z1 gene (CaPPZ1) delays the yeast to hyphae morphological transition [12], and the inhibition of phosphatase could block the development of the more invasive morphological form of Candida [13]. (iv) The unique structural features of the CaPpz1 catalytic domain allow the design of specific inhibitors [8]
Transcriptional shift in the phosphatase mutant strain exaggerates oxidative stress response The deletion of the CaPPZ1 gene generates small changes in RNA synthesis that results in moderate phenotypical changes of slow growth and delayed morphogenesis [12]
Summary
Candida albicans is an opportunistic pathogen which is responsible for widespread nosocomial infections. Medical significance of Candida albicans The opportunistic pathogen Candida yeast colonizes the human body causing slight or undetectable symptoms in healthy individuals. As a last resort to control severe systematic fungal infections amphotericin B can be applied, since it has a wide range of targets and generates a relatively low incidence of resistance [7]. Even this drug has its limitations, as it has toxic side effects [8]. A search for novel fungal drug targets and new ways of antifungal treatments is a well justified research direction
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