scholarly journals Pseudohyphal Regulation by the Transcription Factor Rfg1p in Candida albicans

2010 ◽  
Vol 9 (9) ◽  
pp. 1363-1373 ◽  
Author(s):  
Ian A. Cleary ◽  
Priyadarshini Mulabagal ◽  
Sara M. Reinhard ◽  
Nishant P. Yadev ◽  
Craig Murdoch ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Hyphal Growth ◽  
Growth Conditions ◽  
Pcr Analysis ◽  
Yeast Growth ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Hypha Formation

ABSTRACT The opportunistic human fungal pathogen Candida albicans is a major cause of nosocomial infections. One of the fundamental features of C. albicans pathogenesis is the yeast-to-hypha transition. Hypha formation is controlled positively by transcription factors such as Efg1p and Cph1p, which are required for hyphal growth, and negatively by Tup1p, Rfg1p, and Nrg1p. Previous work by our group has shown that modulating NRG1 gene expression, hence altering morphology, is intimately linked to the capacity of C. albicans to cause disease. To further dissect these virulence mechanisms, we employed the same strategy to analyze the role of Rfg1p in filamentation and virulence. Studies using a tet-RFG1 strain revealed that RFG1 overexpression does not inhibit hypha formation in vitro or in the mouse model of hematogenously disseminated candidiasis. Interestingly, RFG1 overexpression drives formation of pseudohyphae under yeast growth conditions—a phenotype similar to that of C. albicans strains with mutations in one of several mitotic regulatory genes. Complementation assays and real-time PCR analysis indicate that, although the morphology of the tet-RFG1 strain resembles that of the mitotic regulator mutants, Rfg1p overexpression does not impact expression of these genes.

scholarly journals In Vitro Antibiofilm Activity of Eucarobustol E against Candida albicans

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Rui-Huan Liu ◽  
Zhi-Chun Shang ◽  
Tian-Xiao Li ◽  
Ming-Hua Yang ◽  
Ling-Yi Kong
Keyword(s):  
Candida Albicans ◽  
Antifungal Susceptibility ◽  
Hyphal Growth ◽  
Negative Regulator ◽  
Ergosterol Biosynthesis ◽  
Pcr Analysis ◽  
Antibiofilm Activity ◽  
Biofilm Inhibition ◽  
Content Type

ABSTRACT Formyl-phloroglucinol meroterpenoids (FPMs) are important types of natural products with various bioactivities. Our antifungal susceptibility assay showed that one of the Eucalyptus robusta-derived FPMs, eucarobustol E (EE), exerted a strong inhibitory effect against Candida albicans biofilms at a concentration of 16 μg/ml. EE was found to block the yeast-to-hypha transition and reduce the cellular surface hydrophobicity of the biofilm cells. RNA sequencing and real-time reverse transcription-PCR analysis showed that exposure to 16 μg/ml of EE resulted in marked reductions in the levels of expressions of genes involved in hyphal growth (EFG1, CPH1, TEC1, EED1, UME6, and HGC1) and cell surface protein genes (ALS3, HWP1, and SAP5). Interestingly, in response to EE, genes involved in ergosterol biosynthesis were downregulated, while the farnesol-encoding gene (DPP3) was upregulated, and these findings were in agreement with those from the quantification of ergosterol and farnesol. Combined with the obvious elevation of negative regulator genes (TUP1, NRG1), we speculated that EE's inhibition of carbon flow to ergosterol triggered the mechanisms of the negative regulation of hyphal growth and eventually led to biofilm inhibition.

scholarly journals Divergent Targets of Candida albicans Biofilm Regulator Bcr1In VitroandIn Vivo

2012 ◽  
Vol 11 (7) ◽  
pp. 896-904 ◽  
Author(s):  
Saranna Fanning ◽  
Wenjie Xu ◽  
Norma Solis ◽  
Carol A. Woolford ◽  
Scott G. Filler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Stress Response ◽  
Growth Conditions ◽  
Gene Expression Measurement ◽  
Content Type ◽  
New Genes

ABSTRACTCandida albicansis a causative agent of oropharyngeal candidiasis (OPC), a biofilm-like infection of the oral mucosa. Biofilm formation depends upon theC. albicanstranscription factor Bcr1, and previous studies indicate that Bcr1 is required for OPC in a mouse model of infection. Here we have used a nanoString gene expression measurement platform to elucidate the role of Bcr1 in OPC-related gene expression. We chose for assays a panel of 134 genes that represent a range of morphogenetic and cell cycle functions as well as environmental and stress response pathways. We assayed gene expression in whole infected tongue samples. The results sketch a portrait ofC. albicansgene expression in which numerous stress response pathways are activated during OPC. This one set of experiments identifies 64 new genes with significantly altered RNA levels during OPC, thus increasing substantially the number of known genes in this expression class. Thebcr1Δ/Δ mutant had a much more limited gene expression defect during OPC infection than previously reported forin vitrogrowth conditions. Among major functional Bcr1 targets, we observed thatALS3was Bcr1 dependentin vivowhileHWP1was not. We used null mutants and complemented strains to verify that Bcr1 and Hwp1 are required for OPC infection in this model. The role of Als3 is transient and mild, though significant. Our findings suggest that the versatility ofC. albicansas a pathogen may reflect its ability to persist in the face of multiple stresses and underscore that transcriptional circuitry during infection may be distinct from that detailed duringin vitrogrowth.

scholarly journals Disparate Candida albicans Biofilm Formation in Clinical Lipid Emulsions Due to Capric Acid-Mediated Inhibition

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Hubertine M. E. Willems ◽  
Jeremy S. Stultz ◽  
Molly E. Coltrane ◽  
Jabez P. Fortwendel ◽  
Brian M. Peters
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Bloodstream Infections ◽  
Capric Acid ◽  
Lipid Emulsions ◽  
Biofilm Growth ◽  
Content Type ◽  
Biofilm Model ◽  
Hypha Formation

ABSTRACT Receipt of parenteral nutrition (PN) remains an independent risk factor for developing catheter-related bloodstream infections (CR-BSI) caused by fungi, including by the polymorphic fungus Candida albicans, which is notoriously adept at forming drug-resistant biofilm structures. Among a variety of macronutrients, PN solutions contain lipid emulsions to supply daily essential fats and are often delivered via central venous catheters (CVCs). Therefore, using an in vitro biofilm model system, we sought to determine whether various clinical lipid emulsions differentially impacted biofilm growth in C. albicans. We observed that the lipid emulsions Intralipid and Omegaven both stimulated C. albicans biofilm formation during growth in minimal medium or a macronutrient PN solution. Conversely, Smoflipid inhibited C. albicans biofilm formation by approximately 50%. Follow-up studies revealed that while Smoflipid did not impair C. albicans growth, it did significantly inhibit hypha formation and hyphal elongation. Moreover, growth inhibition could be recapitulated in Intralipid when supplemented with capric acid—a fatty acid present in Smoflipid but absent in Intralipid. Capric acid was also found to dose dependently inhibit C. albicans biofilm formation in PN solutions. This is the first study to directly compare different clinical lipid emulsions for their capacity to affect C. albicans biofilm growth. Results derived from this study necessitate further research regarding different lipid emulsions and rates of fungus-associated CR-BSIs.

scholarly journals Physiologic Expression of the Candida albicans Pescadillo Homolog Is Required for Virulence in a Murine Model of Hematogenously Disseminated Candidiasis

2012 ◽  
Vol 11 (12) ◽  
pp. 1552-1556 ◽  
Author(s):  
Priya Uppuluri ◽  
Ashok K. Chaturvedi ◽  
Niketa Jani ◽  
Read Pukkila-Worley ◽  
Carlos Monteagudo ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Murine Model ◽  
Critical Role ◽  
Growth Defect ◽  
Mammalian Host ◽  
Developmental Cycle ◽  
Yeast Growth ◽  
Content Type ◽  
Disseminated Candidiasis

ABSTRACT Morphogenetic conversions contribute to the pathogenesis of Candida albicans invasive infections. Many studies to date have convincingly demonstrated a link between filamentation and virulence; however, relatively little is known regarding the role of the filament-to-yeast transition during the pathogenesis of invasive candidiasis. We previously identified the C. albicans pescadillo homolog ( PES1 ) as essential during yeast growth and growth of lateral yeast on hyphae but not during hyphal growth. Furthermore, we demonstrated that PES1 is required for virulence in vivo in a Galleria mellonella larva model of candidiasis. Here, we have used a regulatable tetO-PES1 / pes1 strain to assess the contribution of C. albicans PES1 to pathogenesis in the commonly used and clinically relevant murine model of hematogenously disseminated candidiasis. Our results indicate that a physiologically controlled level of PES1 expression is required for full virulence in this animal model, with virulence defects observed both when PES1 is overexpressed and and when it is depleted. The pathogenetic defect of cells depleted of PES1 is not due to a general growth defect, as demonstrated by the fact that PES1 -depleted cells still kill Caenorhabditis elegans as efficiently as the wild type due to hyphal outgrowth through worm tissues. Our results suggest a critical role of lateral yeast growth in the ability of C. albicans to normally proliferate within tissues, as well as a pivotal role for Pes1 in the normal developmental cycle of C. albicans within the mammalian host during infection.

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 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 The Candida albicans ATO Gene Family Promotes Neutralization of the Macrophage Phagolysosome

2015 ◽  
Vol 83 (11) ◽  
pp. 4416-4426 ◽  
Author(s):  
Heather A. Danhof ◽  
Michael C. Lorenz
Keyword(s):  
Amino Acids ◽  
Candida Albicans ◽  
Hyphal Growth ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Ph Change ◽  
Content Type ◽  
Ammonia Release ◽  
Hyphal Formation

ABSTRACTCandida albicansis an opportunistic human fungal pathogen that causes a variety of diseases, ranging from superficial mucosal to life-threatening systemic infections, the latter particularly in patients with defects in innate immune function.C. albicanscells phagocytosed by macrophages undergo a dramatic change in their metabolism in which amino acids are a key nutrient. We have shown that amino acid catabolism allows the cell to neutralize the phagolysosome and initiate hyphal growth. We show here that members of the 10-geneATOfamily, which are induced by phagocytosis or the presence of amino acids in an Stp2-dependent manner and encode putative acetate or ammonia transporters, are important effectors of this pH changein vitroand in macrophages. When grown with amino acids as the sole carbon source, the deletion ofATO5or the expression of a dominant-negativeATO1G53Dallele results in a delay in alkalinization, a defect in hyphal formation, and a reduction in the amount of ammonia released from the cell. These strains also form fewer hyphae after phagocytosis, have a reduced ability to escape macrophages, and reside in more acidic phagolysosomal compartments than wild-type cells. Furthermore, overexpression of many of the 10ATOgenes accelerates ammonia release, and anato5Δ ATO1G53Ddouble mutant strain has additive alkalinization and ammonia release defects. Taken together, these results indicate that the Ato protein family is a key mediator of the metabolic changes that allowC. albicansto overcome the macrophage innate immunity barrier.

scholarly journals Environmentally contingent control of Candida albicans cell wall integrity by transcriptional regulator Cup9

Genetics ◽  
2021 ◽  
Author(s):  
Yuichi Ichikawa ◽  
Vincent M Bruno ◽  
Carol A Woolford ◽  
Hannah Kim ◽  
Eunsoo Do ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Surface Protein ◽  
Hyphal Growth ◽  
Growth Conditions ◽  
Cell Wall Integrity ◽  
Yeast Growth ◽  
Transcription Factor Genes ◽  
A Cell ◽  
Rna Levels

Abstract The fungal pathogen Candida albicans is surrounded by a cell wall that is the target of caspofungin and other echinocandin antifungals. C. albicans can grow in several morphological forms, notably budding yeast and hyphae. Yeast and hyphal forms differ in cell wall composition, leading us to hypothesize that there may be distinct genes required for yeast and hyphal responses to caspofungin. Mutants in 27 genes reported previously to be caspofungin hypersensitive under yeast growth conditions were all caspofungin hypersensitive under hyphal growth conditions as well. However, a screen of mutants defective in transcription factor genes revealed that Cup9 is required for normal caspofungin tolerance under hyphal and not yeast growth conditions. In a hyphal-defective efg1Δ/Δ background, Cup9 is still required for normal caspofungin tolerance. This result argues that Cup9 function is related to growth conditions rather than cell morphology. RNA-seq conducted under hyphal growth conditions indicated that 361 genes were up-regulated and 145 genes were down-regulated in response to caspofungin treatment. Both classes of caspofungin-responsive genes were enriched for cell wall-related proteins, as expected for a response to disruption of cell wall integrity and biosynthesis. The cup9Δ/Δ mutant, treated with caspofungin, had reduced RNA levels of 40 caspofungin up-regulated genes, and had increased RNA levels of 8 caspofungin down-regulated genes, an indication that Cup9 has a narrow rather than global role in the cell wall integrity response. Five Cup9-activated surface-protein genes have roles in cell wall integrity, based on mutant analysis published previously (PGA31, IFF11) or shown here (ORF19.3499, ORF19.851 or PGA28), and therefore may explain the hypersensitivity of the cup9Δ/Δ mutant to caspofungin. Our findings define Cup9 as a new determinant of caspofungin susceptibility.

scholarly journals Factors Supporting Cysteine Tolerance and Sulfite Production in Candida albicans

2013 ◽  
Vol 12 (4) ◽  
pp. 604-613 ◽  
Author(s):  
Florian Hennicke ◽  
Maria Grumbt ◽  
Ulrich Lermann ◽  
Nico Ueberschaar ◽  
Katja Palige ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Candida Albicans ◽  
Efflux Pump ◽  
Phenotypic Analysis ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Zinc Cluster ◽  
Enhanced Sensitivity ◽  
Hypha Formation

ABSTRACTThe amino acid cysteine has long been known to be toxic at elevated levels for bacteria, fungi, and humans. However, mechanisms of cysteine tolerance in microbes remain largely obscure. Here we show that the human pathogenic yeastCandida albicansexcretes sulfite when confronted with increasing cysteine concentrations. Mutant construction and phenotypic analysis revealed that sulfite formation from cysteine inC. albicansrelies on cysteine dioxygenase Cdg1, an enzyme with similar functions in humans. Environmental cysteine induced not only the expression of theCDG1gene inC. albicans, but also the expression ofSSU1, encoding a putative sulfite efflux pump. Accordingly, the deletion ofSSU1resulted in enhanced sensitivity of the fungal cells to both cysteine and sulfite. To study the regulation of sulfite/cysteine tolerance in more detail, we screened aC. albicanslibrary of transcription factor mutants in the presence of sulfite. This approach and subsequent independent mutant analysis identified the zinc cluster transcription factor Zcf2 to govern sulfite/cysteine tolerance, as well as cysteine-inducibleSSU1andCDG1gene expression.cdg1Δ andssu1Δ mutants displayed reduced hypha formation in the presence of cysteine, indicating a possible role of the newly proposed mechanisms of cysteine tolerance and sulfite secretion in the pathogenicity ofC. albicans. Moreover,cdg1Δ mutants induced delayed mortality in a mouse model of disseminated infection. Since sulfite is toxic and a potent reducing agent, its production byC. albicanssuggests diverse roles during host adaptation and pathogenicity.

scholarly journals Farnesol and Cyclic AMP Signaling Effects on the Hypha-to-Yeast Transition in Candida albicans

2012 ◽  
Vol 11 (10) ◽  
pp. 1219-1225 ◽  
Author(s):  
Allia K. Lindsay ◽  
Aurélie Deveau ◽  
Amy E. Piispanen ◽  
Deborah A. Hogan
Keyword(s):  
Candida Albicans ◽  
Cyclic Amp ◽  
Fungal Pathogen ◽  
Hyphal Growth ◽  
Morphological Plasticity ◽  
Camp Signaling ◽  
Environmental Cues ◽  
Transcriptional Repressors ◽  
Content Type

ABSTRACTCandida albicans, a fungal pathogen of humans, regulates its morphology in response to many environmental cues and this morphological plasticity contributes to virulence. Farnesol, an autoregulatory molecule produced byC. albicans, inhibits the induction of hyphal growth by inhibiting adenylate cyclase (Cyr1). The role of farnesol and Cyr1 in controlling the maintenance of hyphal growth has been less clear. Here, we demonstrate that preformed hyphae transition to growth as yeast in response to farnesol and that strains with increased cyclic AMP (cAMP) signaling exhibit more resistance to farnesol. Exogenous farnesol did not induce the hypha-to-yeast transition in mutants lacking the Tup1 or Nrg1 transcriptional repressors in embedded conditions. Although body temperature is not required for embedded hyphal growth, we found that the effect of farnesol on the hypha-to-yeast transition varies inversely with temperature. Our model of Cyr1 activity being required for filamentation is also supported by our liquid assay data, which show increased yeast formation when preformed filaments are treated with farnesol. Together, these data suggest that farnesol can modulate morphology in preformed hyphal cells and that the repression of hyphal growth maintenance likely occurs through the inhibition of cAMP signaling.

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