scholarly journals Distinct and Redundant Roles of the Two MYST Histone Acetyltransferases Esa1 and Sas2 in Cell Growth and Morphogenesis of Candida albicans

2013 ◽  
Vol 12 (3) ◽  
pp. 438-449 ◽  
Author(s):  
Xiongjun Wang ◽  
Peng Chang ◽  
Jianping Ding ◽  
Jiangye Chen
Keyword(s):  
Candida Albicans ◽  
Cell Growth ◽  
Histone Acetylation ◽  
Synergistic Effects ◽  
Histone Acetyltransferases ◽  
Content Type ◽  
Functional Roles ◽  
Oxidative Stresses ◽  
Human Body Temperature ◽  
Mutant Cells

ABSTRACTCandida albicansis associated with humans, as both a harmless commensal organism and a pathogen. Adaption to human body temperature is extremely important for its growth and morphogenesis.Saccharomyces cerevisiaeEsa1, a member of the MYST family HATs (histone acetyltransferases) and the catalytic subunit of the NuA4 complex, and its homologues in other eukaryotes have been shown to be essential for cell growth. To investigate the functional roles of two MYST family HATs, Esa1 and Sas2 inC. albicans, we deletedESA1andSAS2in theC. albicansgenome and performed cell growth analyses. Our results demonstrated thatC. albicansEsa1 is not essential for general growth but is essential for filamentous growth. Theesa1/esa1mutant cells exhibited sensitivity to thermal, genotoxic, and oxidative stresses but tolerance to cold, osmotic, and cell wall stresses. In contrast, thesas2/sas2mutant adapted to growth at higher temperatures and promoted filament formation at lower temperatures, resembling the phenotype of aC. albicansstrain overexpressingESA1. Cells with deletions of bothESA1andSAS2were inviable, reflecting the functional redundancy in cell growth.C. albicansEsa1 and Sas2 have distinct and synergistic effects on histone acetylation at H4K5, H4K12, and H4K16. Esa1 contributes mainly to acetylation of H4K5 and H4K12, whereas Sas2 contributes to acetylation of H4K16. Our findings suggest thatC. albicansEsa1 and Sas2 play opposite roles in cell growth and morphogenesis and contribute coordinately to histone acetylation and gene regulation.

scholarly journals Barrier Activity in Candida albicans Mediates Pheromone Degradation and Promotes Mating

2007 ◽  
Vol 6 (6) ◽  
pp. 907-918 ◽  
Author(s):  
Dana Schaefer ◽  
Pierre Côte ◽  
Malcolm Whiteway ◽  
Richard J. Bennett
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
Cell Growth ◽  
Cell Fusion ◽  
Aspartyl Protease ◽  
Wild Type ◽  
Pheromone Activity ◽  
Important Regulator ◽  
Mutant Cells ◽  
Type Strains

ABSTRACT Mating in Candida albicans and Saccharomyces cerevisiae is regulated by the secretion of peptide pheromones that initiate the mating process. An important regulator of pheromone activity in S. cerevisiae is barrier activity, involving an extracellular aspartyl protease encoded by the BAR1 gene that degrades the alpha pheromone. We have characterized an equivalent barrier activity in C. albicans and demonstrate that the loss of C. albicans BAR1 activity results in opaque a cells exhibiting hypersensitivity to alpha pheromone. Hypersensitivity to pheromone is clearly seen in halo assays; in response to alpha pheromone, a lawn of C. albicans Δbar1 mutant cells produces a marked zone in which cell growth is inhibited, whereas wild-type strains fail to show halo formation. C. albicans mutants lacking BAR1 also exhibit a striking mating defect in a cells, but not in α cells, due to overstimulation of the response to alpha pheromone. The block to mating occurs prior to cell fusion, as very few mating zygotes were observed in mixes of Δbar1 a and α cells. Finally, in a barrier assay using a highly pheromone-sensitive strain, we were able to demonstrate that barrier activity in C. albicans is dependent on Bar1p. These studies reveal that a barrier activity to alpha pheromone exists in C. albicans and that the activity is analogous to that caused by Bar1p in S. cerevisiae.

scholarly journals Posttranslational Modifications of Proteins in the Pathobiology of Medically Relevant Fungi

2011 ◽  
Vol 11 (2) ◽  
pp. 98-108 ◽  
Author(s):  
Michelle D. Leach ◽  
Alistair J. P. Brown
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
Cell Growth ◽  
Aspergillus Fumigatus ◽  
Posttranslational Modifications ◽  
Fungal Pathogens ◽  
Content Type ◽  
Cellular Processes ◽  
Peptide Modifications ◽  
Fungal Kingdom

ABSTRACTPosttranslational modifications of proteins drive a wide variety of cellular processes in eukaryotes, regulating cell growth and division as well as adaptive and developmental processes. With regard to the fungal kingdom, most information about posttranslational modifications has been generated through studies of the model yeastsSaccharomyces cerevisiaeandSchizosaccharomyces pombe, where, for example, the roles of protein phosphorylation, glycosylation, acetylation, ubiquitination, sumoylation, and neddylation have been dissected. More recently, information has begun to emerge for the medically important fungal pathogensCandida albicans,Aspergillus fumigatus, andCryptococcus neoformans, highlighting the relevance of posttranslational modifications for virulence. We review the available literature on protein modifications in fungal pathogens, focusing in particular upon the reversible peptide modifications sumoylation, ubiquitination, and neddylation.

scholarly journals O-Mannosylation in Candida albicans Enables Development of Interkingdom Biofilm Communities

mBio ◽  
2014 ◽  
Vol 5 (2) ◽  
Author(s):  
Lindsay C. Dutton ◽  
Angela H. Nobbs ◽  
Katy Jepson ◽  
Mark A. Jepson ◽  
M. Margaret Vickerman ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Biofilm Formation ◽  
Early Stage ◽  
Growth Conditions ◽  
Wild Type ◽  
Content Type ◽  
Subsequent Performance ◽  
Biofilm Development ◽  
Mutant Cells

ABSTRACTCandida albicansis a fungus that colonizes oral cavity surfaces, the gut, and the genital tract.Streptococcus gordoniiis a ubiquitous oral bacterium that has been shown to form biofilm communities withC. albicans. Formation of dual-speciesS. gordonii-C. albicansbiofilm communities involves interaction of theS. gordoniiSspB protein with the Als3 protein on the hyphal filament surface ofC. albicans. Mannoproteins comprise a major component of theC. albicanscell wall, and in this study we sought to determine if mannosylation in cell wall biogenesis ofC. albicanswas necessary for hyphal adhesin functions associated with interkingdom biofilm development. AC. albicans mnt1Δmnt2Δ mutant, with deleted α-1,2-mannosyltransferase genes and thus defective inO-mannosylation, was abrogated in biofilm formation under various growth conditions and produced hyphal filaments that were not recognized byS. gordonii. Cell wall proteomes of hypha-formingmnt1Δmnt2Δ mutant cells showed growth medium-dependent alterations, compared to findings for the wild type, in a range of protein components, including Als1, Als3, Rbt1, Scw1, and Sap9. Hyphal filaments formed bymnt1Δmnt2Δ mutant cells, unlike wild-type hyphae, did not interact withC. albicansAls3 or Hwp1 partner cell wall proteins or withS. gordoniiSspB partner adhesin, suggesting defective functionality of adhesins on themnt1Δmnt2Δ mutant. These observations imply that early stageO-mannosylation is critical for activation of hyphal adhesin functions required for biofilm formation, recognition by bacteria such asS. gordonii, and microbial community development.IMPORTANCEIn the human mouth, microorganisms form communities known as biofilms that adhere to the surfaces present.Candida albicansis a fungus that is often found within these biofilms. We have focused on the mechanisms by whichC. albicansbecomes incorporated into communities containing bacteria, such asStreptococcus. We find that impairment of early stage addition of mannose sugars toC. albicanshyphal filament proteins deleteriously affects their subsequent performance in mediating formation of polymicrobial biofilms. Our analyses provide new understanding of the way that microbial communities develop, and of potential means to controlC. albicansinfections.

scholarly journals N -Acetylglucosamine (GlcNAc)-Inducible Gene GIG2 Is a Novel Component of GlcNAc Metabolism in Candida albicans

2013 ◽  
Vol 13 (1) ◽  
pp. 66-76 ◽  
Author(s):  
Swagata Ghosh ◽  
Kongara Hanumantha Rao ◽  
Neel Sarovar Bhavesh ◽  
Gobardhan Das ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Carbon Sources ◽  
Transcriptional Responses ◽  
Content Type ◽  
Metabolic Intermediates ◽  
Catabolic Genes ◽  
Opportunistic Fungal Pathogen ◽  
Targeted Inhibition ◽  
Mutant Cells ◽  
Insight Into

ABSTRACT Candida albicans is an opportunistic fungal pathogen that resides in the human body as a commensal and can turn pathogenic when the host is immunocompromised. Adaptation of C. albicans to host niche-specific conditions is important for the establishment of pathogenicity, where the ability of C. albicans to utilize multiple carbon sources provides additional flexibility. One alternative sugar is N -acetylglucosamine (GlcNAc), which is now established as an important carbon source for many pathogens and can also act as a signaling molecule. Although GlcNAc catabolism has been well studied in many pathogens, the importance of several enzymes involved in the formation of metabolic intermediates still remains elusive. In this context, microarray analysis was carried out to investigate the transcriptional responses induced by GlcNAc under different conditions. A novel gene that was highly upregulated immediately following the GlcNAc catabolic genes was identified and was named GIG2 (GlcNAc-induced gene 2). This gene is regulated in a manner distinct from that of the GlcNAc-induced genes described previously in that GlcNAc metabolism is essential for its induction. Furthermore, this gene is involved in the metabolism of N -acetylneuraminate (sialic acid), a molecule equally important for initial host-pathogen recognition. Mutant cells showed a considerable decrease in fungal burden in mouse kidneys and were hypersensitive to oxidative stress conditions. Since GIG2 is also present in many other fungal and enterobacterial genomes, targeted inhibition of its activity would offer insight into the treatment of candidiasis and other fungal or enterobacterial infections.

scholarly journals Effects of Echinocandins in Combination with Nikkomycin Z against Invasive Candida albicans Bloodstream Isolates and the fks Mutants

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Yuk-Yam Cheung ◽  
Mamie Hui
Keyword(s):  
Candida Albicans ◽  
Therapeutic Potential ◽  
Synergistic Effects ◽  
Rank Test ◽  
Content Type ◽  
Log Rank Test ◽  
Echinocandin Resistance ◽  
Nikkomycin Z

ABSTRACT We evaluated the in vitro and in vivo effects of nikkomycin Z combined with an echinocandin (anidulafungin or micafungin) against two Candida albicans isolates and their lab-derived echinocandin-resistant fks mutants with FKS1 S645Y and FKS1 S645P. Synergistic effects were observed in all tested strains (fractional inhibitory concentration index, <0.5). Enhanced survival was observed in an immunocompromised murine model (log-rank test, P < 0.02). Our study demonstrated the therapeutic potential of nikkomycin Z-echinocandin combinations in managing echinocandin resistance.

scholarly journals Normal Adaptation of Candida albicans to the Murine Gastrointestinal Tract Requires Efg1p-Dependent Regulation of Metabolic and Host Defense Genes

2012 ◽  
Vol 12 (1) ◽  
pp. 37-49 ◽  
Author(s):  
Jessica V. Pierce ◽  
Daniel Dignard ◽  
Malcolm Whiteway ◽  
Carol A. Kumamoto
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Ectopic Expression ◽  
Dependent Manner ◽  
Null Mutant ◽  
Gi Tract ◽  
Transcriptional Responses ◽  
Content Type ◽  
Opportunistic Fungal Pathogen ◽  
Mutant Cells

ABSTRACTAlthough gastrointestinal colonization by the opportunistic fungal pathogenCandida albicansis generally benign, severe systemic infections are thought to arise due to escape of commensalC. albicansfrom the gastrointestinal (GI) tract. TheC. albicanstranscription factor Efg1p is a major regulator of GI colonization, hyphal morphogenesis, and virulence. The goals of this study were to identify the Efg1p regulon during GI tract colonization and to compareC. albicansgene expression during colonization of different organs of the GI tract. Our results identified significant differences in gene expression between cells colonizing the cecum and ileum. During colonization,efg1−null mutant cells expressed higher levels of genes involved in lipid catabolism, carnitine biosynthesis, and carnitine utilization than did colonizing wild-type (WT) cells. In addition, during laboratory growth,efg1−null mutant cells grew to a higher density than WT cells. Theefg1−null mutant grew in depleted medium, while WT cells could grow only if the depleted medium was supplemented with carnitine, a compound that promotes the metabolism of fatty acids. Altered gene expression and altered growth capability support the ability ofefg1−cells to hypercolonize naïve mice. Also, Efg1p was shown to be important for transcriptional responses to the stresses present in the cecum environment. For example, during colonization,SOD5, encoding a superoxide dismutase, was highly upregulated in an Efg1p-dependent manner. Ectopic expression ofSOD5in anefg1−null mutant increased the fitness of theefg1−null mutant cells during colonization. These data show thatEFG1is an important regulator of GI colonization.

Histone acetylation/deacetylation in Candida albicans and their potential as antifungal targets

2020 ◽  
Vol 15 (11) ◽  
pp. 1075-1090
Author(s):  
Shan Su ◽  
Xiuyun Li ◽  
Xinmei Yang ◽  
Yiman Li ◽  
Xueqi Chen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Histone Acetylation ◽  
Stress Responses ◽  
Histone Deacetylases ◽  
Fungal Pathogen ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Histone Acetyltransferases ◽  
Opportunistic Fungal Pathogen

Recently, the incidence of invasive fungal infections has significantly increased. Candida albicans (C. albicans) is the most common opportunistic fungal pathogen that infects humans. The limited number of available antifungal agents and the emergence of drug resistance pose difficulties to treatment, thus new antifungals are urgently needed. Through their functions in DNA replication, DNA repair and transcription, histone acetyltransferases (HATs) and histone deacetylases (HDACs) perform essential functions relating to growth, virulence, drug resistance and stress responses of C. albicans. Here, we summarize the physiological and pathological functions of HATs/HDACs, potential antifungal targets and underlying antifungal compounds that impact histone acetylation and deacetylation. We anticipate this review will stimulate the identification of new HAT/HDAC-related antifungal targets and antifungal agents.

scholarly journals The Synergistic Effect of Azoles and Fluoxetine against Resistant Candida albicans Strains Is Attributed to Attenuating Fungal Virulence

2016 ◽  
Vol 60 (10) ◽  
pp. 6179-6188 ◽  
Author(s):  
Wenrui Gu ◽  
Dongmei Guo ◽  
Liuping Zhang ◽  
Dongmei Xu ◽  
Shujuan Sun
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Synergistic Effects ◽  
Mechanism Study ◽  
Content Type ◽  
Expression Levels ◽  
Time Kill ◽  
Gene Expression Levels

ABSTRACTThis study evaluated the synergistic effects of the selective serotonin reuptake inhibitor, fluoxetine, in combination with azoles againstCandida albicansbothin vitroandin vivoand explored the underlying mechanism. MICs, sessile MICs, and time-kill curves were determined for resistantC. albicans.Galleria mellonellawas used as a nonvertebrate model for determining the efficacy of the drug combinations againstC. albicansin vivo. For the mechanism study, gene expression levels of theSAPgene family were determined by reverse transcription (RT)-PCR, and extracellular phospholipase activities were detectedin vitroby the egg yolk agar method. The combinations resulted in synergistic activity againstC. albicansstrains, but the same effect was not found for the non-albicans Candidastrains. For the biofilms formed over 4, 8, and 12 h, synergism was seen for the combination of fluconazole and fluoxetine. In addition, the time-kill curves confirmed the synergism dynamically. The results of theG. mellonellastudies agreed with thein vitroanalysis. In the mechanism study, we observed that fluconazole plus fluoxetine caused downregulation of the gene expression levels ofSAP1toSAP4and weakened the extracellular phospholipase activities of resistantC. albicans. The combinations of azoles and fluoxetine showed synergistic effects against resistantC. albicansmay diminish the virulence properties ofC. albicans.

scholarly journals In VitroAnalyses of the Effects of Heparin and Parabens on Candida albicans Biofilms and Planktonic Cells

2011 ◽  
Vol 56 (1) ◽  
pp. 148-153 ◽  
Author(s):  
Marisa H. Miceli ◽  
Stella M. Bernardo ◽  
T. S. Neil Ku ◽  
Carla Walraven ◽  
Samuel A. Lee
Keyword(s):  
Candida Albicans ◽  
Metabolic Activity ◽  
Biofilm Formation ◽  
High Dose ◽  
Dependent Manner ◽  
Planktonic Cells ◽  
Content Type ◽  
Heparin Sodium ◽  
The Individual

ABSTRACTInfections and thromboses are the most common complications associated with central venous catheters. Suggested strategies for prevention and management of these complications include the use of heparin-coated catheters, heparin locks, and antimicrobial lock therapy. However, the effects of heparin onCandida albicansbiofilms and planktonic cells have not been previously studied. Therefore, we sought to determine thein vitroeffect of a heparin sodium preparation (HP) on biofilms and planktonic cells ofC. albicans. Because HP contains two preservatives, methyl paraben (MP) and propyl paraben (PP), these compounds and heparin sodium without preservatives (Pure-H) were also tested individually. The metabolic activity of the mature biofilm after treatment was assessed using XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction and microscopy. Pure-H, MP, and PP caused up to 75, 85, and 60% reductions of metabolic activity of the mature preformedC. albicansbiofilms, respectively. Maximal efficacy against the mature biofilm was observed with HP (up to 90%) compared to the individual compounds (P< 0.0001). Pure-H, MP, and PP each inhibitedC. albicansbiofilm formation up to 90%. A complete inhibition of biofilm formation was observed with HP at 5,000 U/ml and higher. When tested against planktonic cells, each compound inhibited growth in a dose-dependent manner. These data indicated that HP, MP, PP, and Pure-H havein vitroantifungal activity againstC. albicansmature biofilms, formation of biofilms, and planktonic cells. Investigation of high-dose heparin-based strategies (e.g., heparin locks) in combination with traditional antifungal agents for the treatment and/or prevention ofC. albicansbiofilms is warranted.

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