scholarly journals Self-Induction ofa/aor α/α Biofilms in Candida albicans Is a Pheromone-Based Paracrine System Requiring Switching

2011 ◽  
Vol 10 (6) ◽  
pp. 753-760 ◽  
Author(s):  
Song Yi ◽  
Nidhi Sahni ◽  
Karla J. Daniels ◽  
Kevin L. Lu ◽  
Guanghua Huang ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mating Type ◽  
Biofilm Formation ◽  
Receptor Gene ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cell Type ◽  
Opposite Mating Type ◽  
Content Type ◽  
Α Pheromone

ABSTRACTLikeMTL-heterozygous (a/α) cells, whiteMTL-homozygous (a/aor α/α) cells ofCandida albicans, to which a minority of opaque cells of opposite mating type have been added, form thick, robust biofilms. The latter biofilms are uniquely stimulated by the pheromone released by opaque cells and are regulated by the mitogen-activated protein kinase signal transduction pathway. However, whiteMTL-homozygous cells, to which opaque cells of opposite mating type have not been added, form thinner biofilms. Mutant analyses reveal that these latter biofilms are self-induced. Self-induction ofa/abiofilms requires expression of the α-receptor geneSTE2and the α-pheromone geneMFα, and self-induction of α/α biofilms requires expression of thea-receptor geneSTE3and thea-pheromone geneMFa. In both cases, deletion ofWOR1, the master switch gene, blocks cells in the white phenotype and biofilm formation, indicating that self-induction depends upon low frequency switching from the white to opaque phenotype. These results suggest a self-induction scenario in which minority opaquea/acells formed by switching secrete, in a mating-type-nonspecific fashion, α-pheromone, which stimulates biofilm formation through activation of the α-pheromone receptor of majority whitea/acells. A similar scenario is suggested for a white α/α cell population, in which minority opaque α/α cells secretea-pheromone. This represents a paracrine system in which one cell type (opaque) signals a second highly related cell type (white) to undergo a complex response, in this case the formation of a unisexual white cell biofilm.

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 Synergistic Interaction between Candida albicans and Commensal Oral Streptococci in a NovelIn VitroMucosal Model

2011 ◽  
Vol 80 (2) ◽  
pp. 620-632 ◽  
Author(s):  
Patricia I. Diaz ◽  
Zhihong Xie ◽  
Takanori Sobue ◽  
Angela Thompson ◽  
Basak Biyikoglu ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Gastrointestinal Tract ◽  
Oral Mucosa ◽  
Biofilm Formation ◽  
Salivary Flow ◽  
Flow Cell ◽  
Synergistic Interaction ◽  
Esophageal Mucosa ◽  
Oral Streptococci ◽  
Content Type

ABSTRACTCandida albicansis a commensal colonizer of the gastrointestinal tract of humans, where it coexists with highly diverse bacterial communities. It is not clear whether this interaction limits or promotes the potential ofC. albicansto become an opportunistic pathogen. Here we investigate the interaction betweenC. albicansand three species of streptococci from the viridans group, which are ubiquitous and abundant oral commensal bacteria. The ability ofC. albicansto form biofilms withStreptococcus oralis,Streptococcus sanguinis, orStreptococcus gordoniiwas investigated using flow cell devices that allow abiotic biofilm formation under salivary flow. In addition, we designed a novel flow cell system that allows mucosal biofilm formation under conditions that mimic the environment in the oral and esophageal mucosae. It was observed thatC. albicansand streptococci formed a synergistic partnership whereC. albicanspromoted the ability of streptococci to form biofilms on abiotic surfaces or on the surface of an oral mucosa analogue. The increased ability of streptococci to form biofilms in the presence ofC. albicanscould not be explained by a growth-stimulatory effect since the streptococci were unaffected in their growth in planktonic coculture withC. albicans. Conversely, the presence of streptococci increased the ability ofC. albicansto invade organotypic models of the oral and esophageal mucosae under conditions of salivary flow. Moreover, characterization of mucosal invasion by the biofilm microorganisms suggested that the esophageal mucosa is more permissive to invasion than the oral mucosa. In summary,C. albicansand commensal oral streptococci display a synergistic interaction with implications for the pathogenic potential ofC. albicansin the upper gastrointestinal tract.

scholarly journals The Unfolded Protein Response Regulates Pathogenic Development of Ustilago maydis by Rok1-Dependent Inhibition of Mating-Type Signaling

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Lara Schmitz ◽  
Melina Ayaka Schwier ◽  
Kai Heimel
Keyword(s):  
Unfolded Protein Response ◽  
Mating Type ◽  
Ustilago Maydis ◽  
Mitogen Activated Protein Kinase ◽  
In Planta ◽  
Fungal Virulence ◽  
Content Type ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Fungal pathogens require the unfolded protein response (UPR) to maintain protein homeostasis of the endoplasmic reticulum (ER) during pathogenic development. In the corn smut fungus Ustilago maydis, pathogenic development is controlled by the a and b mating-type loci. The UPR is specifically activated after plant penetration and required for efficient secretion of effectors and suppression of the plant defense response. The interaction between the UPR regulator Cib1 and the central developmental regulator Clp1 modulates the pathogenic program and triggers fungal colonization of the host plant. By contrast, when activated before plant penetration, the UPR interferes with fungal virulence by reducing expression of bE and bW, the central regulators of pathogenic development encoded by the b mating-type locus. Here, we show that this inhibitory effect results from UPR-mediated suppression of the pheromone response pathway upstream of the b regulatory network. UPR activity prompts dephosphorylation of the pheromone-responsive mitogen-activated protein kinase (MAPK) Kpp2, reducing activity of the pheromone response factor Prf1 that regulates expression of bE and bW. Deletion of the dual specificity phosphatase rok1 fully suppressed UPR-dependent inhibition of Kpp2 phosphorylation, formation of infectious filaments, and fungal virulence. Rok1 determines the activity of mating-type signaling pathways and thus the degree of fungal virulence. We propose that UPR-dependent regulation of Rok1 aligns ER physiology with fungal aggressiveness and effector gene expression during biotrophic growth of U. maydis in the host plant. IMPORTANCE The unfolded protein response (UPR) is crucial for endoplasmic reticulum (ER) homeostasis and disease development in fungal pathogens. In the plant-pathogenic fungus Ustilago maydis, the UPR supports fungal proliferation in planta and effector secretion for plant defense suppression. In this study, we uncovered that UPR activity, which is normally restricted to the biotrophic stage in planta, inhibits mating and the formation of infectious filaments by Rok1-dependent dephosphorylation of the pheromone responsive mitogen-activated protein kinase (MAPK) Kpp2. This observation is relevant for understanding how the fungal virulence program is regulated by cellular physiology. UPR-mediated control of mating-type signaling pathways predicts that effector gene expression and the virulence potential are controlled by ER stress levels.

scholarly journals An Amyloid Core Sequence in the Major Candida albicans Adhesin Als1p Mediates Cell-Cell Adhesion

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Vida Ho ◽  
Philippe Herman-Bausier ◽  
Christopher Shaw ◽  
Karen A. Conrad ◽  
Melissa C. Garcia-Sherman ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Cell Adhesion ◽  
Cell Surface ◽  
Biofilm Formation ◽  
Force Spectroscopy ◽  
Cell Aggregation ◽  
Analysis Tool ◽  
Content Type ◽  
Core Sequence ◽  
Cell Cell

ABSTRACT The human fungal commensal Candida albicans can become a serious opportunistic pathogen in immunocompromised hosts. The C. albicans cell adhesion protein Als1p is a highly expressed member of a large family of paralogous adhesins. Als1p can mediate binding to epithelial and endothelial cells, is upregulated in infections, and is important for biofilm formation. Als1p includes an amyloid-forming sequence at amino acids 325 to 331, identical to the sequence in the paralogs Als5p and Als3p. Therefore, we mutated Val326 to test whether this sequence is important for activity. Wild-type Als1p (Als1pWT) and Als1p with the V326N mutation (Als1pV326N) were expressed at similar levels in a Saccharomyces cerevisiae surface display model. Als1pV326N cells adhered to bovine serum albumin (BSA)-coated beads similarly to Als1pWT cells. However, cells displaying Als1pV326N showed visibly smaller aggregates and did not fluoresce in the presence of the amyloid-binding dye Thioflavin-T. A new analysis tool for single-molecule force spectroscopy-derived surface mapping showed that statistically significant force-dependent Als1p clustering occurred in Als1pWT cells but was absent in Als1pV326N cells. In single-cell force spectroscopy experiments, strong cell-cell adhesion was dependent on an intact amyloid core sequence on both interacting cells. Thus, the major adhesin Als1p interacts through amyloid-like β-aggregation to cluster adhesin molecules in cis on the cell surface as well as in trans to form cell-cell bonds. IMPORTANCE Microbial cell surface adhesins control essential processes such as adhesion, colonization, and biofilm formation. In the opportunistic fungal pathogen Candida albicans, the agglutinin-like sequence (ALS) gene family encodes eight cell surface glycoproteins that mediate adherence to biotic and abiotic surfaces and cell-cell aggregation. Als proteins are critical for commensalism and virulence. Their activities include attachment and invasion of endothelial and epithelial cells, morphogenesis, and formation of biofilms on host tissue and indwelling medical catheters. At the molecular level, Als5p-mediated cell-cell aggregation is dependent on the formation of amyloid-like nanodomains between Als5p-expressing cells. A single-site mutation to valine 326 abolishes cellular aggregation and amyloid formation. Our results show that the binding characteristics of Als1p follow a mechanistic model similar to Als5p, despite its differential expression and biological roles.

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 Candida albicans Cek1 Mitogen-Activated Protein Kinase Signaling Enhances Fungicidal Activity of Salivary Histatin 5

2015 ◽  
Vol 59 (6) ◽  
pp. 3460-3468 ◽  
Author(s):  
Rui Li ◽  
Sumant Puri ◽  
Swetha Tati ◽  
Paul J. Cullen ◽  
Mira Edgerton
Keyword(s):  
Candida Albicans ◽  
Protein Kinase ◽  
Antifungal Drugs ◽  
Mitogen Activated Protein Kinase ◽  
Fungal Cell ◽  
Content Type ◽  
Histatin 5 ◽  
Mitogen Activated Protein ◽  
Hyphal Formation ◽  
Sensor Proteins

ABSTRACTCandida albicansis a major etiological organism for oropharyngeal candidiasis (OPC), while salivary histatin 5 (Hst 5) is a human fungicidal protein that protects the oral cavity from OPC.C. albicanssenses its environment by mitogen-activated protein kinase (MAPK) activation that can also modulate the activity of some antifungal drugs, including Hst 5. We found that phosphorylation of the MAPK Cek1, induced either byN-acetylglucosamine (GlcNAc) or serum, or its constitutive activation by deletion of its phosphatase Cpp1 elevated the susceptibility ofC. albicanscells to Hst 5. Cek1 phosphorylation but not hyphal formation was needed for increased Hst 5 sensitivity. Interference with the Cek1 pathway by deletion of its head sensor proteins, Msb2 and Sho1, or by addition of secreted aspartyl protease (SAP) cleavage inhibitors, such as pepstatin A, reduced Hst 5 susceptibility under Cek1-inducing conditions. Changes in fungal cell surface glycostructures also modulated Hst 5 sensitivity, and Cek1-inducing conditions resulted in a higher uptake rate of Hst 5. These results show that there is a consistent relationship between activation of Cek1 MAPK and increased Hst 5 susceptibility inC. albicans.

scholarly journals Asexual Propagation of a Virulent Clone Complex in a Human and Feline Outbreak of Sporotrichosis

2014 ◽  
Vol 14 (2) ◽  
pp. 158-169 ◽  
Author(s):  
Marcus de Melo Teixeira ◽  
Anderson Messias Rodrigues ◽  
Clement K. M. Tsui ◽  
Luiz Gonzaga Paulo de Almeida ◽  
Anne D. Van Diepeningen ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Mating Type ◽  
Sequence Data ◽  
Fungal Infections ◽  
Haplotype Diversity ◽  
Sporothrix Schenckii ◽  
Mitogen Activated Protein Kinase ◽  
Comparative Genomic ◽  
Asexual Propagation ◽  
Content Type

ABSTRACT Sporotrichosis is one of the most frequent subcutaneous fungal infections in humans and animals caused by members of the plant-associated, dimorphic genus Sporothrix . Three of the four medically important Sporothrix species found in Brazil have been considered asexual as no sexual stage has ever been reported in Sporothrix schenckii , Sporothrix brasiliensis , or Sporothrix globosa . We have identified the mating type ( MAT ) loci in the S. schenckii (strain 1099-18/ATCC MYA-4821) and S. brasiliensis (strain 5110/ATCC MYA-4823) genomes by using comparative genomic approaches to determine the mating type ratio in these pathogen populations. Our analysis revealed the presence of a MAT1-1 locus in S. schenckii while a MAT1-2 locus was found in S. brasiliensis representing genomic synteny to other Sordariomycetes . Furthermore, the components of the mitogen-activated protein kinase (MAPK)-pheromone pathway, pheromone processing enzymes, and meiotic regulators have also been identified in the two pathogens, suggesting the potential for sexual reproduction. The ratio of MAT1-1 to MAT1-2 was not significantly different from 1:1 for all three Sporothrix species, but the population of S. brasiliensis in the outbreaks originated from a single mating type. We also explored the population genetic structure of these pathogens using sequence data of two loci to improve our knowledge of the pattern of geographic distribution, genetic variation, and virulence phenotypes. Population genetics data showed significant population differentiation and clonality with a low level of haplotype diversity in S. brasiliensis isolates from different regions of sporotrichosis outbreaks in Brazil. In contrast, S. schenckii isolates demonstrated a high degree of genetic variability without significant geographic differentiation, indicating the presence of recombination. This study demonstrated that two species causing the same disease have contrasting reproductive strategies and genetic variability patterns.

scholarly journals Investigating the Function of Ddr48p in Candida albicans

2012 ◽  
Vol 11 (6) ◽  
pp. 718-724 ◽  
Author(s):  
I. A. Cleary ◽  
N. B. MacGregor ◽  
S. P. Saville ◽  
D. P. Thomas
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
The United States ◽  
Pathogenic Potential ◽  
Content Type ◽  
General Stress Response ◽  
Damage Response ◽  
Sense And Respond ◽  
Immune Defects

ABSTRACTCandidiasis now represents the fourth most frequent nosocomial infection both in the United States and worldwide.Candida albicansis an increasingly common threat to human health as a consequence of AIDS, steroid therapy, organ and tissue transplantation, cancer therapy, broad-spectrum antibiotics, and other immune defects. The pathogenic potential ofC. albicansis intimately related to certain key processes, including biofilm formation and filamentation. Ddr48p is a damage response protein that is significantly upregulated during both biofilm formation and filamentation, but its actual function is unknown. Previous studies have indicated that this protein may be essential inC. albicansbut notSaccharomyces cerevisiae. Here we examined the function of Ddr48p and investigated the role of this protein in biofilm formation and filamentation. We demonstrated that this protein is not essential inC. albicansand appears to be dispensable for filamentation. However,DDR48is required for the flocculation response stimulated by 3-aminotriazole-induced amino acid starvation. Furthermore, we examined the response of this deletion strain to a wide variety of environmental stressors and antifungal compounds. We observed several mild sensitivity or resistance phenotypes and also found that Ddr48p contributes to the DNA damage response ofC. albicans. The results of this study reveal that the role of this highly expressed protein goes beyond a general stress response and impinges on a key facet of pathogenesis, namely, the ability to sense and respond to changes in the host environment.

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