scholarly journals The Transcriptional Regulator Nrg1p Controls Candida albicans Biofilm Formation and Dispersion

2010 ◽  
Vol 9 (10) ◽  
pp. 1531-1537 ◽  
Author(s):  
Priya Uppuluri ◽  
Christopher G. Pierce ◽  
Derek P. Thomas ◽  
Sarah S. Bubeck ◽  
Stephen P. Saville ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Structural Integrity ◽  
Genetically Engineered ◽  
Negative Regulator ◽  
Yeast Cells ◽  
Developmental Cycle ◽  
Content Type ◽  
Adhesive Interactions

ABSTRACT The ability of Candida albicans to reversibly switch morphologies is important for biofilm formation and dispersion. In this pathogen, Nrg1p functions as a key negative regulator of the yeast-to-hypha morphogenetic transition. We have previously described a genetically engineered C. albicans tet-NRG1 strain in which NRG1 expression levels can be manipulated by the presence or absence of doxycycline (DOX). Here, we have used this strain to ascertain the role of Nrg1p in regulating the different stages of the C. albicans biofilm developmental cycle. In an in vitro model of biofilm formation, the C. albicans tet-NRG1 strain was able to form mature biofilms only when DOX was present in the medium, but not in the absence of DOX, when high levels of NRG1 expression blocked the yeast-to-hypha transition. However, in a biofilm cell retention assay in which biofilms were developed with mixtures of C. albicans tet-NRG1 and SC5314 strains, tet-NRG1 yeast cells were still incorporated into the mixed biofilms, in which an intricate network of hyphae of the wild-type strain provided for biofilm structural integrity and adhesive interactions. Also, utilizing an in vitro biofilm model under conditions of flow, we demonstrated that C. albicans Nrg1p exerts an exquisite control of the dispersal process, as overexpression of NRG1 leads to increases in dispersion of yeast cells from the biofilms. Our results demonstrate that manipulation of NRG1 gene expression has a profound influence on biofilm formation and biofilm dispersal, thus identifying Nrg1p as a key regulator of the C. albicans biofilm life cycle.

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.

scholarly journals The “Finger,” a Unique Multicellular Morphology of Candida albicans Induced by CO2and Dependent upon the Ras1-Cyclic AMP Pathway

2012 ◽  
Vol 11 (10) ◽  
pp. 1257-1267 ◽  
Author(s):  
Karla J. Daniels ◽  
Claude Pujol ◽  
Thyagarajan Srikantha ◽  
David R. Soll
Keyword(s):  
Candida Albicans ◽  
Cyclic Amp ◽  
Mutational Analysis ◽  
Cell Monolayer ◽  
Yeast Cells ◽  
Content Type ◽  
Dispersal Mechanism ◽  
Basal Bulb ◽  
High Doses

ABSTRACTMost experiments exploring the basic biology of pathogenic microbes are performedin vitrounder conditions that do not usually mimic those of their host niche. Hence, developmental programs initiated by specific host cues may be missedin vitro. We have tested the effects of growing low-density agar cultures of the yeast pathogenCandida albicansin concentrations of CO2found in the gastrointestinal tract. It is demonstrated that in physiological concentrations of CO2at 37°C, yeast cells form a heretofore undescribed multicellular “finger” morphology distinct from a previously described stalk-like structure induced by high doses of UV irradiation that kills more than 99.99% of cells. The finger extends aerially, is uniform in diameter, and is visible to the naked eye, attaining lengths of 3 mm. It is composed of a basal yeast cell monolayer adhering to a semispherical crater formed in the agar and connected to a basal bulb of yeast cells at a fragile interface. The bulb extends into the long shaft. We propose that a single, centrally located hypha extending the length of the shaft forms buds at compartment junctions that serve as the source of the yeast cells in the shaft. A mutational analysis reveals finger formation is dependent upon the pathway Ras1→Cdc35→cyclic AMP (cAMP) (PDE2—|)→Tpk2→Tec1. Because of the mechanically fragile interface and the compactness of bulb and shaft, we suggest that the finger may function as a multicellular dispersal mechanism produced in host niches containing high levels of CO2.

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 Targeting Fibronectin To Disrupt In Vivo Candida albicans Biofilms

2016 ◽  
Vol 60 (5) ◽  
pp. 3152-3155 ◽  
Author(s):  
Jeniel E. Nett ◽  
Jonathan Cabezas-Olcoz ◽  
Karen Marchillo ◽  
Deane F. Mosher ◽  
David R. Andes
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Drug Targets ◽  
Venous Catheter ◽  
Surface Adhesion ◽  
Inhibitory Protein ◽  
Content Type ◽  
Novel Target

ABSTRACTNew drug targets are of great interest for the treatment of fungal biofilms, which are routinely resistant to antifungal therapies. We theorized that the interaction ofCandida albicanswith matricellular host proteins would provide a novel target. Here, we show that an inhibitory protein (FUD) targetingCandida-fibronectin interactions disrupts biofilm formationin vitroandin vivoin a rat venous catheter model. The peptide appears to act by blocking the surface adhesion ofCandida, halting biofilm formation.

scholarly journals Oral Administration of the Broad-Spectrum Antibiofilm Compound Toremifene Inhibits Candida albicans and Staphylococcus aureus Biofilm FormationIn Vivo

2014 ◽  
Vol 58 (12) ◽  
pp. 7606-7610 ◽  
Author(s):  
Kaat De Cremer ◽  
Nicolas Delattin ◽  
Katrijn De Brucker ◽  
Annelies Peeters ◽  
Soña Kucharíková ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Candida Albicans ◽  
Broad Spectrum ◽  
Staphylococcus Epidermidis ◽  
Biofilm Formation ◽  
Candida Krusei ◽  
Content Type ◽  
And Staphylococcus Aureus

ABSTRACTWe here report on thein vitroactivity of toremifene to inhibit biofilm formation of different fungal and bacterial pathogens, includingCandida albicans,Candida glabrata,Candida dubliniensis,Candida krusei,Pseudomonas aeruginosa,Staphylococcus aureus, andStaphylococcus epidermidis. We validated thein vivoefficacy of orally administered toremifene againstC. albicans and S. aureusbiofilm formation in a rat subcutaneous catheter model. Combined, our results demonstrate the potential of toremifene as a broad-spectrum oral antibiofilm compound.

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 The Heat-Induced Molecular Disaggregase Hsp104 of Candida albicans Plays a Role in Biofilm Formation and Pathogenicity in a Worm Infection Model

2012 ◽  
Vol 11 (8) ◽  
pp. 1012-1020 ◽  
Author(s):  
Alessandro Fiori ◽  
Soňa Kucharíková ◽  
Gilmer Govaert ◽  
Bruno P. A. Cammue ◽  
Karin Thevissen ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Stress Responses ◽  
Biofilm Formation ◽  
Fungal Pathogens ◽  
Elevated Temperatures ◽  
Structural Defects ◽  
Infection Model ◽  
Content Type

ABSTRACT The consequences of deprivation of the molecular chaperone Hsp104 in the fungal pathogen Candida albicans were investigated. Mutants lacking HSP104 became hypersusceptible to lethally high temperatures, similarly to the corresponding mutants of Saccharomyces cerevisiae , whereas normal susceptibility was restored upon reintroduction of the gene. By use of a strain whose only copy of HSP104 is an ectopic gene under the control of a tetracycline-regulated promoter, expression of Hsp104 prior to the administration of heat shock could be demonstrated to be sufficient to confer protection from the subsequent temperature increase. This result points to a key role for Hsp104 in orchestrating the cell response to elevated temperatures. Despite their not showing evident growth or morphological defects, biofilm formation by cells lacking HSP104 proved to be defective in two established in vitro models that use polystyrene and polyurethane as the substrates. Biofilms formed by the wild-type and HSP104 -reconstituted strains showed patterns of intertwined hyphae in the extracellular matrix. In contrast, biofilm formed by the hsp104 Δ/ hsp104 Δ mutant showed structural defects and appeared patchy and loose. Decreased virulence of the hsp104 Δ/ hsp104 Δ mutant was observed in the Caenorhabditis elegans infection model, in which high in vivo temperature does not play a role. In agreement with the view that stress responses in fungal pathogens may have evolved to provide niche-specific adaptation to environmental conditions, these results provide an indication of a temperature-independent role for Hsp104 in support of Candida albicans virulence, in addition to its key role in governing thermotolerance.

scholarly journals Sustained Nitric Oxide-Releasing Nanoparticles Induce Cell Death in Candida albicans Yeast and Hyphal Cells, Preventing Biofilm FormationIn Vitroand in a Rodent Central Venous Catheter Model

2016 ◽  
Vol 60 (4) ◽  
pp. 2185-2194 ◽  
Author(s):  
Mohammed S. Ahmadi ◽  
Hiu Ham Lee ◽  
David A. Sanchez ◽  
Adam J. Friedman ◽  
Moses T. Tar ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Candida Albicans ◽  
Flow Cytometric Analysis ◽  
Extracellular Polysaccharide ◽  
Host Cells ◽  
Yeast Cells ◽  
Central Venous ◽  
Content Type ◽  
Biofilm Development

ABSTRACTCandida albicansis a leading nosocomial pathogen. Today, candidal biofilms are a significant cause of catheter infections, and such infections are becoming increasingly responsible for the failure of medical-implanted devices.C. albicansforms biofilms in which fungal cells are encased in an autoproduced extracellular polysaccharide matrix. Consequently, the enclosed fungi are protected from antimicrobial agents and host cells, providing a unique niche conducive to robust microbial growth and a harbor for recurring infections. Here we demonstrate that a recently developed platform comprised of nanoparticles that release therapeutic levels of nitric oxide (NO-np) inhibits candidal biofilm formation, destroys the extracellular polysaccharide matrices of mature fungal biofilms, and hinders biofilm development on surface biomaterials such as the lumen of catheters. We found NO-np to decrease both the metabolic activity of biofilms and the cell viability ofC. albicansin vitroandin vivo. Furthermore, flow cytometric analysis found NO-np to induce apoptosis in biofilm yeast cellsin vitro. Moreover, NO-np behave synergistically when used in combination with established antifungal drug therapies. Here we propose NO-np as a novel treatment modality, especially in combination with standard antifungals, for the prevention and/or remediation of fungal biofilms on central venous catheters and other medical devices.

scholarly journals Filamentation Is Associated with Reduced Pathogenicity of Multiple Non-albicans Candida Species

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Mohua Banerjee ◽  
Anna L. Lazzell ◽  
Jesus A. Romo ◽  
Jose L. Lopez-Ribot ◽  
David Kadosh
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Transcriptional Profiling ◽  
Genetically Engineered ◽  
Dramatic Reduction ◽  
Content Type ◽  
Fungal Burden ◽  
The Relationship

ABSTRACT Candidiasis affects a wide variety of immunocompromised and medically compromised patients. Candida albicans, a major human fungal pathogen, accounts for about 50% of all cases, while the remainder are caused by the less pathogenic non-albicans Candida species (NACS). These species are believed to be less pathogenic, in part, because they do not filament as readily or robustly as C. albicans, although definitive evidence is lacking. To address this question, we used strains for two NACS, Candida tropicalis and Candida parapsilosis, which were genetically engineered to constitutively express the key transcriptional regulator UME6 and drive strong filamentation both in vitro and during infection in vivo. Unexpectedly, both strains showed a dramatic reduction in organ fungal burden in response to UME6 expression. Consistent with these findings, we observed that a C. tropicalis hyperfilamentous mutant was significantly reduced and a filamentation-defective mutant was slightly increased for organ fungal burden. Comprehensive immune profiling generally did not reveal any significant changes in the host response to UME6 expression in the NACS that could explain the increased clearance of infection. Interestingly, whole-genome transcriptional profiling indicated that while genes important for filamentation were induced by UME6 expression in C. tropicalis and C. parapsilosis, other genes involved in a variety of processes important for pathogenesis were strongly downregulated. These findings suggest that there are fundamental evolutionary differences in the relationship between morphology and pathogenicity among Candida species and that NACS do not necessarily possess the same virulence properties as C. albicans. IMPORTANCE Many immunocompromised individuals, including HIV/AIDS and cancer patients, are susceptible to candidiasis. About half of all cases are caused by the major fungal pathogen Candida albicans, whereas the remainder are due to less pathogenic non-albicans Candida species (NACS). Generation of filamentous cells represents a major virulence property of C. albicans, and the NACS are believed to be less pathogenic, in part, because they do not filament as well as C. albicans does. To address this question, we determined the pathogenicity of two NACS strains that have been genetically engineered to promote filamentation during infection. Surprisingly, these strains showed a dramatic reduction in pathogenicity. The host immune response did not appear to be affected. However, unlike C. albicans, filamentation of the NACS was associated with downregulation of several genes important for pathogenicity processes. Our results suggest that there are fundamental evolutionary differences in the relationship between filamentation and pathogenesis in NACS compared to C. albicans.

scholarly journals RNA aptamers selected against yeast cells inhibit Candida albicans biofilm formation in vitro

2019 ◽  
Vol 8 (8) ◽  
Author(s):  
Boy M. Bachtiar ◽  
Chatchawan Srisawat ◽  
Endang W. Bachtiar
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Rna Aptamers ◽  
Yeast Cells
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