scholarly journals Ras1 involved in the antifungal resistance of Candida albicans and the inhibition of farnesol on the resistance of biofilms

2019 ◽  
Author(s):  
Xin Wei ◽  
Lulu Zuo ◽  
Shengyan Chen ◽  
Zhenzhen Zhang ◽  
Liuliu Jiang
Keyword(s):  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Hyphal Growth ◽  
Antifungal Resistance ◽  
Morphological Observation ◽  
Inhibitory Effects ◽  
Wild Strains ◽  
Almost All ◽  
Candida Albicans Biofilms

Abstract Background: Farnesol enhances the susceptibility of Candida albicans biofilms to antifungals, while the molecular mechanisms of this behavior are poorly understood. RAS1 regulates the hyphal growth of C. albicans, and farnesol inhibited hyphal growth by RAS1 regulation, while the role of RAS1 in the resistance of C. albicans biofilms and the molecular mechanism of the RAS1 in the farnesol-relevant antifungal capacity to C. albicans biofilms is still unknown. The study hypothesized that Ras1 involved in the antifungal resistance of C. albicans and the inhibition of farnesol on the resistance of biofilms. Results: The susceptibility assays showed that RAS1 over-expressing strain (RAS1OE) increased the resistance of C.albicans in both planktonic and biofilm form to antifungals, while RAS1 deletion strain (ras1Δ/Δ) reduced that to antifungals. The SMIC50 of the antifungals were increased with the mature of the biofilms formed from the mutant and the wild strains. Exogenous farnesol decreased the resistance of RAS1OE to antifungals, including fluconazole, amphotericin B, itraconazole, caspofungin, terbinafine, 5-flurocytosine and nystatin. The inhibitory effects of farnesol on the antifungal resistance of the biofilms from the RAS1OE were in accordance to almost all of the growth phases. Moreover, exogenous farnesol decreased the resistance of biofilms from RAS1OE more obviously than that from the wild strains (P<0.05). In addition, Morphological observation showed that that RAS1OE increased hyphal growth the biofilms, while ras1Δ/Δ reduced that of the biofilms. Compare to the wild-type strain, the inhibitory effects of farnesol on hyphal growth were more obvious to the RAS1OE, while less obvious to the ras1Δ/Δ. Furthermore, farnesol reduced the level of Ras1 and the expression of RAS1 of the biofilms formed from the RAS1OE strain compared with those of the untreated controls at all studied phases. Moreover, farnesol reduced the level of Ras1 and the expression of RAS1 of the biofilms formed from RAS1OE more obviously than that from the wild strains. Conclusions: Ras1 involved in the antifungal resistance of Candida albicans, and the inhibition of farnesol on the resistance of biofilm.

scholarly journals Adaptations of the Secretome of Candida albicans in Response to Host-Related Environmental Conditions

2015 ◽  
Vol 14 (12) ◽  
pp. 1165-1172 ◽  
Author(s):  
Frans M. Klis ◽  
Stanley Brul
Keyword(s):  
Candida Albicans ◽  
Cell Surface ◽  
Human Body ◽  
Environmental Conditions ◽  
Surface Stress ◽  
Hyphal Growth ◽  
Content Type ◽  
General Response ◽  
Culture Supernatants

ABSTRACTThe wall proteome and the secretome of the fungal pathogenCandida albicanshelp it to thrive in multiple niches of the human body. Mass spectrometry has allowed researchers to study the dynamics of both subproteomes. Here, we discuss some major responses of the secretome to host-related environmental conditions. Three β-1,3-glucan-modifying enzymes, Mp65, Sun41, and Tos1, are consistently found in large amounts in culture supernatants, suggesting that they are needed for construction and expansion of the cell wall β-1,3-glucan layer and thus correlate with growth and might serve as diagnostic biomarkers. The genesENG1,CHT3, andSCW11, which encode an endoglucanase, the major chitinase, and a β-1,3-glucan-modifying enzyme, respectively, are periodically expressed and peak in M/G1. The corresponding protein abundances in the medium correlate with the degree of cell separation during single-yeast-cell, pseudohyphal, and hyphal growth. We also discuss the observation that cells treated with fluconazole, or other agents causing cell surface stress, form pseudohyphal aggregates. Fluconazole-treated cells secrete abundant amounts of the transglucosylase Phr1, which is involved in the accumulation of β-1,3-glucan in biofilms, raising the question whether this is a general response to cell surface stress. Other abundant secretome proteins also contribute to biofilm formation, emphasizing the important role of secretome proteins in this mode of growth. Finally, we discuss the relevance of these observations to therapeutic intervention. Together, these data illustrate thatC. albicansactively adapts its secretome to environmental conditions, thus promoting its survival in widely divergent niches of the human body.

scholarly journals Rac1 and Cdc42 Have Different Roles in Candida albicans Development

2006 ◽  
Vol 5 (2) ◽  
pp. 321-329 ◽  
Author(s):  
Martine Bassilana ◽  
Robert A. Arkowitz
Keyword(s):  
Candida Albicans ◽  
Plasma Membrane ◽  
G Protein ◽  
Fluorescence Recovery After Photobleaching ◽  
Hyphal Growth ◽  
Opportunistic Pathogen ◽  
Filamentous Growth ◽  
Fluorescence Recovery

ABSTRACT We investigated the role of the highly conserved G protein Rac1 in the opportunistic pathogen Candida albicans. We identified and disrupted RAC1 and show here that, in contrast to CDC42, it is not necessary for viability or serum-induced hyphal growth but is essential for filamentous growth when cells are embedded in a matrix. Rac1 is localized to the plasma membrane, yet its distribution is more homogenous than that of Cdc42, with no enrichment at the tips of either buds or hyphae. In addition, fluorescence recovery after photobleaching results indicate that Rac1 and Cdc42 have different dynamics at the membrane. Furthermore, overexpression of Rac1 does not complement Cdc42 function, and conversely, overexpression of Cdc42 does not complement Rac1 function. Thus, Rac1 and Cdc42, although highly similar to one another, have different roles in C. albicans development.

scholarly journals Candida albicans Ume6, a Filament-Specific Transcriptional Regulator, Directs Hyphal Growth via a Pathway Involving Hgc1 Cyclin-Related Protein

2010 ◽  
Vol 9 (9) ◽  
pp. 1320-1328 ◽  
Author(s):  
Patricia L. Carlisle ◽  
David Kadosh
Keyword(s):  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Constitutive Expression ◽  
Transcriptional Regulator ◽  
Hyphal Growth ◽  
Related Protein ◽  
Content Type ◽  
Epistasis Analysis ◽  
Dependent Inactivation ◽  
Hyphal Formation

ABSTRACT The ability of Candida albicans, the most common human fungal pathogen, to transition from yeast to hyphae is essential for pathogenicity. While a variety of transcription factors important for filamentation have been identified and characterized, links between transcriptional regulators of C. albicans morphogenesis and molecular mechanisms that drive hyphal growth are not well defined. We have previously observed that constitutive expression of UME6, which encodes a filament-specific transcriptional regulator, is sufficient to direct hyphal growth in the absence of filament-inducing conditions. Here we show that HGC1, encoding a cyclin-related protein necessary for hyphal growth under filament-inducing conditions, is specifically important for agar invasion, hyphal extension, and formation of true septa in response to constitutive UME6 expression under non-filament-inducing conditions. HGC1-dependent inactivation of Rga2, a Cdc42 GTPase activating protein (GAP), also appears to be important for these processes. In response to filament-inducing conditions, HGC1 is induced prior to UME6 although UME6 controls the level and duration of HGC1 expression, which are likely to be important for hyphal extension. Interestingly, an epistasis analysis suggests that UME6 and HGC1 play distinct roles during early filament formation. These findings establish a link between a key regulator of filamentation and a downstream mechanism important for hyphal formation. In addition, this study demonstrates that a strain expressing constitutive high levels of UME6 provides a powerful strategy to specifically dissect downstream mechanisms important for hyphal development in the absence of complex filament-inducing conditions.

scholarly journals Filamentation in Candida albicans is modulated by adaptive translation of farnesol signalling genes

2021 ◽  
Author(s):  
Carla Oliveira ◽  
Ana Rita Guimarães ◽  
Inês Correia ◽  
Inês Sousa ◽  
Ana Poim ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Phenotypic Diversity ◽  
Critical Role ◽  
Normal Growth ◽  
Morphological Diversity ◽  
Growth Conditions ◽  
Response To Stress ◽  
Variable Morphology

AbstractThe complex biology of the human pathogen Candida albicans is reflected in its remarkable ability to proliferate in numerous body sites, adapt to drastic changes in the environment, form various types of colonies and grow in yeast, pseudo-hyphal and hyphal forms. Much has been learnt in recent years about the relevance of this phenotypic plasticity, but the mechanisms that support it are still not fully understood. We have demonstrated that atypical translation of the CUG codon is a source of unexpected morphological diversity. The CUG codon is translated as both leucine (Leu) (~3%) and serine (Ser) (~97%) in normal growth conditions, but Ser/Leu levels change in response to stress. Remarkably, recombinant C. albicans strains incorporating between 20% and 99% of Leu at CUG sites display a diverse array of phenotypes and produce colonies of variable morphology containing a mixture of yeast, pseudohyphal and hyphal cells. In this work we investigate the role of the CUG codon in the yeast-hypha transition. Our data show that increasing incorporation levels of Leu at CUG sites trigger hyphal initiation under non-inducing conditions by reducing farnesol production, and increasing the degradation of the Nrg1 hyphal repressor. We propose that dual CUG Ser/Leu translation triggers filamentation via the Nrg1 pathway.ImportanceThe unique translation of the CUG codon as both Ser (~97%) and Leu (~3%) plays a key role in the production of high genomic and phenotypic diversity in C. albicans. The molecular mechanisms that support such diversity are poorly understood. Here, we show that increased Leu incorporation at CUG sites induce hyphae formation in media where C. albicans normally grows in the yeast form. The data show that increasing Leu at CUG sites triggers the degradation of the hyphal repressor Nrg1, allowing for full expression of hyphal genes. Since filamentation is important for invasion of host tissues, this work shows how the atypical translation of a single codon may play a critical role in the virulence of all fungi of the CTG clade.

scholarly journals Isoform-Selective NFAT Inhibitor: Potential Usefulness and Development

2021 ◽  
Vol 22 (5) ◽  
pp. 2725
Author(s):  
Noriko Kitamura ◽  
Osamu Kaminuma
Keyword(s):  
T Cells ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Family Members ◽  
Activated T Cells ◽  
Structural Abnormalities ◽  
Structural Differences ◽  
Almost All

Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological events. Therefore, functional and/or structural abnormalities of NFAT are linked to the pathogenesis of diseases in various organs. The NFAT protein family consists of five isoforms, and each isoform performs diverse functions and has unique expression patterns in the target tissues. This diversity has made it difficult to obtain ideal pharmacological output for immunosuppressants that inhibit the activity of almost all NFAT family members, causing serious and wide-ranging side effects. Moreover, it remains unclear whether isoform-selective NFAT regulation can be achieved by targeting the structural differences among NFAT isoforms and whether this strategy can lead to the development of better drugs than the existing ones. This review summarizes the role of the NFAT family members in biological events, including the development of various diseases, as well as the usefulness of and problems associated with NFAT-targeting therapies, including those dependent on current immunosuppressants. Finally, we propose a novel therapeutic strategy based on the molecular mechanisms that enable selective regulation of specific NFAT isoforms.

Inhibitory effects of the essential oils α-longipinene and linalool on biofilm formation and hyphal growth of Candida albicans

Biofouling ◽  
2017 ◽  
Vol 33 (2) ◽  
pp. 143-155 ◽  
Author(s):  
Ranjith Kumar Manoharan ◽  
Jin-Hyung Lee ◽  
Yong-Guy Kim ◽  
Soon-Il Kim ◽  
Jintae Lee
Keyword(s):  
Candida Albicans ◽  
Essential Oils ◽  
Biofilm Formation ◽  
Hyphal Growth ◽  
Inhibitory Effects

scholarly journals Role of Transcription Factor CaNdt80p in Cell Separation, Hyphal Growth, and Virulence in Candida albicans

2010 ◽  
Vol 9 (4) ◽  
pp. 634-644 ◽  
Author(s):  
Adnane Sellam ◽  
Christopher Askew ◽  
Elias Epp ◽  
Faiza Tebbji ◽  
Alaka Mullick ◽  
...  
Keyword(s):  
Cell Wall ◽  
Transcription Factor ◽  
Candida Albicans ◽  
Cell Separation ◽  
Hyphal Growth ◽  
Functional Domain ◽  
Transcription Factor Family ◽  
Content Type ◽  
Genes Encoding

ABSTRACT The NDT80/PhoG transcription factor family includes ScNdt80p, a key modulator of the progression of meiotic division in Saccharomyces cerevisiae. In Candida albicans, a member of this family, CaNdt80p, modulates azole sensitivity by controlling the expression of ergosterol biosynthesis genes. We previously demonstrated that CaNdt80p promoter targets, in addition to ERG genes, were significantly enriched in genes related to hyphal growth. Here, we report that CaNdt80p is indeed required for hyphal growth in response to different filament-inducing cues and for the proper expression of genes characterizing the filamentous transcriptional program. These include noteworthy genes encoding cell wall components, such as HWP1, ECE1, RBT4, and ALS3. We also show that CaNdt80p is essential for the completion of cell separation through the direct transcriptional regulation of genes encoding the chitinase Cht3p and the cell wall glucosidase Sun41p. Consistent with their hyphal defect, ndt80 mutants are avirulent in a mouse model of systemic candidiasis. Interestingly, based on functional-domain organization, CaNdt80p seems to be a unique regulator characterizing fungi from the CTG clade within the subphylum Saccharomycotina. Therefore, this study revealed a new role of the novel member of the fungal NDT80 transcription factor family as a regulator of cell separation, hyphal growth, and virulence.

scholarly journals Role of dimorphism in the development of Candida albicans biofilms

1999 ◽  
Vol 48 (7) ◽  
pp. 671-679 ◽  
Author(s):  
GEORGE S. BAILLIE ◽  
L. JULIA DOUGLAS
Keyword(s):  
Candida Albicans ◽  
Candida Albicans Biofilms

scholarly journals A Forkhead Transcription Factor Is Important for True Hyphal as well as Yeast Morphogenesis in Candida albicans

2002 ◽  
Vol 1 (5) ◽  
pp. 787-798 ◽  
Author(s):  
Eric S. Bensen ◽  
Scott G. Filler ◽  
Judith Berman
Keyword(s):  
Cell Cycle ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Hyphal Growth ◽  
Growth Conditions ◽  
Yeast Cells ◽  
Cycle Progression ◽  
Forkhead Transcription Factors

ABSTRACT Candida albicans is an important pathogen of immunocompromised patients which grows with true hyphal, pseudohyphal, and yeast morphologies. The dynamics of cell cycle progression are markedly different in true hyphal relative to pseudohyphal and yeast cells, including nuclear movement and septin ring positioning. In Saccharomyces cerevisiae, two forkhead transcription factors (ScFKH1 and ScFKH2) regulate the expression of B-cyclin genes. In both S. cerevisiae and Schizosaccharomyces pombe, forkhead transcription factors also influence morphogenesis. To explore the molecular mechanisms that connect C. albicans morphogenesis with cell cycle progression, we analyzed CaFKH2, the single homolog of S. cerevisiae FKH1/FKH2. C. albicans cells lacking CaFkh2p formed constitutive pseudohyphae under all yeast and hyphal growth conditions tested. Under hyphal growth conditions levels of hyphae-specific mRNAs were reduced, and under yeast growth conditions levels of several genes encoding proteins likely to be important for cell wall separation were reduced. Together these results imply that Fkh2p is required for the morphogenesis of true hyphal as well as yeast cells. Efg1p and Cph1p, two transcription factors that contribute to C. albicans hyphal growth, were not required for the pseudohyphal morphology of fkh2 mutants, implying that Fkh2p acts in pathways downstream of and/or parallel to Efg1p and Cph1p. In addition, cells lacking Fkh2p were unable to damage human epithelial or endothelial cells in vitro, suggesting that Fkh2p contributes to C. albicans virulence.

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