scholarly journals Mds3 Regulates Morphogenesis in Candida albicans through the TOR Pathway

2010 ◽  
Vol 30 (14) ◽  
pp. 3695-3710 ◽  
Author(s):  
Lucia F. Zacchi ◽  
Jonatan Gomez-Raja ◽  
Dana A. Davis
Keyword(s):  
Candida Albicans ◽  
Ribosomal Proteins ◽  
Ph Sensing ◽  
Tor Pathway ◽  
Preferential Expression ◽  
Human Fungal Pathogen ◽  
Expression Of Genes ◽  
Mucosal Surfaces ◽  
Genes Encoding ◽  
Morphological Defects

ABSTRACT The success of Candida albicans as a major human fungal pathogen is dependent on its ability to colonize and survive as a commensal on diverse mucosal surfaces. One trait required for survival and virulence in the host is the morphogenetic yeast-to-hypha transition. Mds3 was identified as a regulator of pH-dependent morphogenesis that functions in parallel with the classic Rim101 pH-sensing pathway. Microarray analyses revealed that mds3Δ/Δ cells had an expression profile indicative of a hyperactive TOR pathway, including the preferential expression of genes encoding ribosomal proteins and a decreased expression of genes involved in nitrogen source utilization. The transcriptional and morphological defects of the mds3Δ/Δ mutant were rescued by rapamycin, an inhibitor of TOR, and this rescue was lost in strains carrying the rapamycin-resistant TOR1-1 allele or an rbp1Δ/Δ deletion. Rapamycin also rescued the transcriptional and morphological defects associated with the loss of Sit4, a TOR pathway effector, but not the loss of Rim101 or Ras1. The sit4Δ/Δ and mds3Δ/Δ mutants had additional phenotypic similarities, suggesting that Sit4 and Mds3 function similarly in the TOR pathway. Finally, we found that Mds3 and Sit4 coimmunoprecipitate. Thus, Mds3 is a new member of the TOR pathway that contributes to morphogenesis in C. albicans as a regulator of this key morphogenetic pathway.

scholarly journals Tolerance to fluconazole in Candida albicans is regulated by temperature and aneuploidy

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
FENG YANG ◽  
YUANYING JIANG ◽  
JUDITH BERMAN
Keyword(s):  
Candida Albicans ◽  
High Temperature ◽  
Fungal Pathogen ◽  
Drug Tolerance ◽  
Antifungal Drugs ◽  
Clinical Isolates ◽  
Human Fungal Pathogen ◽  
Genes Encoding ◽  
Aneuploid Chromosome ◽  
Definition Of

Candida albicans is a prevalent human fungal pathogen. Azoles are the most widely used antifungal drugs. Drug tolerance in bacteria is well defined and thoroughly studied, but in fungi, the definition of drug tolerance and the mechanism that drive it are not well understood. Here, we found that a large proportion of clinical isolates were intrinsically tolerant to fluconazole, and/or could be induced by high temperature (37°C) to become tolerant (conditionally tolerant). When treated with inhibitory doses of fluconazole, non-tolerant strains became tolerant by forming aneuploids involving different chromosomes, with chromosome R duplication as the most recurrent mechanism. Tolerance determines the ability to grow in the presence of fluconazole and other azoles, in a manner independent of the MIC. Both temperature conditional tolerance and the associated aneuploidy were sensitive to FK506, an inhibitor of calcineurin. Intrinsic and conditional tolerance were also abolished by deletions of genes encoding the calcineurin (CMP1 and CNB1). However, the dependence of tolerance on calcineurin could be bypassed by a different aneuploid chromosome. Thus, fluconazole tolerance in C. albicans is regulated by temperature and by aneuploidy and is dependent upon aneuploidy, but this dependence can be bypassed by an additional aneuploidy.

scholarly journals Cell Cycle Dynamics and Quorum Sensing in Candida albicans Chlamydospores Are Distinct from Budding and Hyphal Growth

2005 ◽  
Vol 4 (7) ◽  
pp. 1191-1202 ◽  
Author(s):  
Stephen W. Martin ◽  
Lois M. Douglas ◽  
James B. Konopka
Keyword(s):  
Candida Albicans ◽  
Quorum Sensing ◽  
Hyphal Growth ◽  
Distinct Type ◽  
Positive Role ◽  
Human Fungal Pathogen ◽  
Morphological Defects ◽  
Greater Curvature ◽  
Cell Cycle Dynamics ◽  
Suspensor Cells

ABSTRACT The regulation of morphogenesis in the human fungal pathogen Candida albicans is under investigation to better understand how the switch between budding and hyphal growth is linked to virulence. Therefore, in this study we examined the ability of C. albicans to undergo a distinct type of morphogenesis to form large thick-walled chlamydospores whose role in infection is unclear, but they act as a resting form in other species. During chlamydospore morphogenesis, cells switch to filamentous growth and then develop elongated suspensor cells that give rise to chlamydospores. These filamentous cells were distinct from true hyphae in that they were wider and were not inhibited by the quorum-sensing factor farnesol. Instead, farnesol increased chlamydospore production, indicating that quorum sensing can also have a positive role. Nuclear division did not occur across the necks of chlamydospores, as it does in budding. Interestingly, nuclei divided within the suspensor cells, and then one daughter nucleus subsequently migrated into the chlamydospore. Septins were not detected near mitotic nuclei but were localized at chlamydospore necks. At later stages, septins localized throughout the chlamydospore plasma membrane and appeared to form long filamentous structures. Deletion of the CDC10 or CDC11 septins caused greater curvature of cells growing in a filamentous manner and morphological defects in suspensor cells and chlamydospores. These studies identify aspects of chlamydospore morphogenesis that are distinct from bud and hyphal morphogenesis.

scholarly journals Release from Quorum-Sensing Molecules Triggers Hyphal Formation during Candida albicans Resumption of Growth

2005 ◽  
Vol 4 (7) ◽  
pp. 1203-1210 ◽  
Author(s):  
Brice Enjalbert ◽  
Malcolm Whiteway
Keyword(s):  
Candida Albicans ◽  
Quorum Sensing ◽  
Culture Medium ◽  
Pathogenic Fungus ◽  
Hyphal Growth ◽  
Growth Environment ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Hyphal Formation ◽  
Cyclin Genes

ABSTRACT Candida albicans is a pathogenic fungus able to change morphology in response to variations in its growth environment. Simple inoculation of stationary cells into fresh medium at 37°C, without any other manipulations, appears to be a powerful but transient inducer of hyphal formation; this process also plays a significant role in classical serum induction of hyphal formation. The mechanism appears to involve the release of hyphal repression caused by quorum-sensing molecules in the growth medium of stationary-phase cells, and farnesol has a strong but incomplete role in this process. We used DNA microarray technology to study both the resumption of growth of Candida albicans cells and molecular regulation involving farnesol. Maintaining farnesol in the culture medium during the resumption of growth both delays and reduces the induction of hypha-related genes yet triggers expression of genes encoding drug efflux components. The persistence of farnesol also prevents the repression of histone genes during hyphal growth and affects the expression of putative or demonstrated morphogenesis-regulating cyclin genes, such as HGC1, CLN3, and PCL2. The results suggest a model explaining the triggering of hyphae in the host based on quorum-sensing molecules.

scholarly journals A Glucose Sensor in Candida albicans

2006 ◽  
Vol 5 (10) ◽  
pp. 1726-1737 ◽  
Author(s):  
Victoria Brown ◽  
Jessica A. Sexton ◽  
Mark Johnston
Keyword(s):  
Candida Albicans ◽  
Glucose Sensor ◽  
Glucose Sensing ◽  
Glucose Sensors ◽  
Glucose Levels ◽  
High Affinity ◽  
Expression Of Genes ◽  
Hexose Transporters ◽  
Genes Encoding ◽  
Sensor Glucose

ABSTRACT The Hgt4 protein of Candida albicans (orf19.5962) is orthologous to the Snf3 and Rgt2 glucose sensors of Saccharomyces cerevisiae that govern sugar acquisition by regulating the expression of genes encoding hexose transporters. We found that HGT4 is required for glucose induction of the expression of HGT12, HXT10, and HGT7, which encode apparent hexose transporters in C. albicans. An hgt4Δ mutant is defective for growth on fermentable sugars, which is consistent with the idea that Hgt4 is a sensor of glucose and similar sugars. Hgt4 appears to be sensitive to glucose levels similar to those in human serum (∼5 mM). HGT4 expression is repressed by high levels of glucose, which is consistent with the idea that it encodes a high-affinity sugar sensor. Glucose sensing through Hgt4 affects the yeast-to-hyphal morphological switch of C. albicans cells: hgt4Δ mutants are hypofilamented, and a constitutively signaling form of Hgt4 confers hyperfilamentation of cells. The hgt4Δ mutant is less virulent than wild-type cells in a mouse model of disseminated candidiasis. These results suggest that Hgt4 is a high-affinity glucose sensor that contributes to the virulence of C. albicans.

scholarly journals Heme Competition Triggers an Increase in the Pathogenic Potential of Porphyromonas gingivalis in Porphyromonas gingivalis-Candida albicans Mixed Biofilm

2020 ◽  
Vol 11 ◽  
Author(s):  
Yanyang Guo ◽  
Yu Wang ◽  
Yijin Wang ◽  
Yabing Jin ◽  
Chen Wang
Keyword(s):  
Candida Albicans ◽  
Porphyromonas Gingivalis ◽  
Morphological Changes ◽  
Single Species ◽  
Healthy Human ◽  
Pathogenic Potential ◽  
Expression Of Genes ◽  
Gene Level ◽  
Genes Encoding ◽  
Laser Confocal Microscope

As one of the main pathogens of periodontitis, Porphyromonas gingivalis often forms mixed biofilms with other bacteria or fungi under the gingiva, such as Candida albicans. Heme is an important iron source for P. gingivalis and C. albicans that supports their growth in the host. From the perspective of heme competition, this study aims to clarify that the competition for heme enhances the pathogenic potential of P. gingivalis during the interaction between P. gingivalis and C. albicans. Porphyromonas gingivalis single-species biofilm and P. gingivalis-C. albicans dual-species biofilm were established in a low- and high-heme environment. The results showed that the vitality of P. gingivalis was increased in the dual-species biofilm under the condition of low heme, and the same trend was observed under a laser confocal microscope. Furthermore, the morphological changes in P. gingivalis were observed by electron microscope, and the resistance of P. gingivalis in dual-species biofilm was stronger against the killing effect of healthy human serum and antibiotics. The ability of P. gingivalis to agglutinate erythrocyte was also enhanced in dual-species biofilm. These changes disappeared when heme was sufficient, which confirmed that heme competition was the cause of thepathogenicy change in P. gingivalis. Gene level analysis showed that P. gingivalis was in a superior position in the competition relationship by increasing the expression of heme utilization-related genes, such as HmuY, HmuR, HusA, and Tlr. In addition, the expression of genes encoding gingipains (Kgp, RgpA/B) was also significantly increased. They not only participate in the process of utilizing heme, but also are important components of the virulence factors of P. gingivalis. In conclusion, our results indicated that the pathogenic potential of P. gingivalis was enhanced by C. albicans through heme competition, which ultimately promoted the occurrence and development of periodontitis and, therefore, C. albicans subgingival colonization should be considered as a factor in assessing the risk of periodontitis.

scholarly journals Genome-Wide Expression Profiling of the Response to Azole, Polyene, Echinocandin, and Pyrimidine Antifungal Agents in Candida albicans

2005 ◽  
Vol 49 (6) ◽  
pp. 2226-2236 ◽  
Author(s):  
Teresa T. Liu ◽  
Robin E. B. Lee ◽  
Katherine S. Barker ◽  
Richard E. Lee ◽  
Lai Wei ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Ergosterol Biosynthesis ◽  
Reverse Transcription Pcr ◽  
Expression Of Genes ◽  
Lipid Fatty Acid ◽  
Genes Encoding ◽  
Molecule Transport ◽  
Small Molecule Transport

ABSTRACT Antifungal agents exert their activity through a variety of mechanisms, some of which are poorly understood. We examined changes in the gene expression profile of Candida albicans following exposure to representatives of the four currently available classes of antifungal agents used in the treatment of systemic fungal infections. Ketoconazole exposure increased expression of genes involved in lipid, fatty acid, and sterol metabolism, including NCP1, MCR1, CYB5, ERG2, ERG3, ERG10, ERG25, ERG251, and that encoding the azole target, ERG11. Ketoconazole also increased expression of several genes associated with azole resistance, including CDR1, CDR2, IFD4, DDR48, and RTA3. Amphotericin B produced changes in the expression of genes involved in small-molecule transport (ENA21), and in cell stress (YHB1, CTA1, AOX1, and SOD2). Also observed was decreased expression of genes involved in ergosterol biosynthesis, including ERG3 and ERG11. Caspofungin produced changes in expression of genes encoding cell wall maintenance proteins, including the β-1,3-glucan synthase subunit GSL22, as well as PHR1, ECM21, ECM33, and FEN12. Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21. Real-time reverse transcription-PCR was used to confirm microarray results. Genes responding similarly to two or more drugs were also identified. These data shed new light on the effects of these classes of antifungal agents on C. albicans.

scholarly journals The DYRK1A protein kinase regulates ribosome mass and translation rates through transcriptional control of ribosomal protein genes expression

2021 ◽  
Author(s):  
Chiara Di Vona ◽  
Laura Barba ◽  
Roberto Ferrari ◽  
Susana de la Luna
Keyword(s):  
Ribosomal Proteins ◽  
Transcriptional Control ◽  
Protein Translation ◽  
Ribosomal Protein Genes ◽  
Expression Of Genes ◽  
Specific Subset ◽  
Cell Proliferation And Differentiation ◽  
Dual Specificity ◽  
Global Protein Synthesis ◽  
Genes Encoding

ABSTRACTRibosomal proteins (RPs) are evolutionary conserved proteins that are essential for protein translation. RP expression must be tightly regulated, both to ensure the appropriate assembly of ribosomes and to respond to the growth demands of cells. The elements regulating the transcription of RP genes (RPGs) have been characterized in yeast and Drosophila, yet how cells regulate the production of RPs in mammals is less well understood. The dual-specificity tyrosine-regulated kinase 1A (DYRK1A) is known to participate in cell proliferation and differentiation in mammals, and its dysregulation is associated with disease in humans. Here, we show that DYRK1A marks a specific subset of proximal RPG promoters, which are characterized by the presence of the palindromic TCTCGCGAGA motif. The presence of DYRK1A at these promoters is associated with enhanced binding of the TATA-binding protein, TBP, and it is negatively correlated with the binding of the GABP transcription factor, establishing at least two clusters of RPGs that could be coordinately regulated. Indeed, DYRK1A depletion leads to a reduction of both RP mRNA and protein. Significantly, cells in which DYRK1A is depleted have fewer ribosomes, reduced global protein synthesis and they are smaller. Based on these results, we propose a novel role for DYRK1A in coordinating the expression of genes encoding RPs, thereby controlling cell growth in mammals.

scholarly journals The Transcription Factor Homolog CTF1 Regulates β-Oxidation in Candida albicans

2009 ◽  
Vol 8 (10) ◽  
pp. 1604-1614 ◽  
Author(s):  
Melissa A. Ramírez ◽  
Michael C. Lorenz
Keyword(s):  
Candida Albicans ◽  
Carbon Metabolism ◽  
Regulatory Network ◽  
Glyoxylate Cycle ◽  
Carbon Sources ◽  
Microbial Pathogens ◽  
Peroxisomal Biogenesis ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
The Glyoxylate Cycle

ABSTRACT Carbon starvation is one of the many stresses to which microbial pathogens are subjected while in the host. Pathways necessary for the utilization of alternative carbon sources, such as gluconeogenesis, the glyoxylate cycle, and β-oxidation of fatty acids, have been shown to be required for full virulence in several systems, including the fungal pathogen Candida albicans. We have investigated the regulatory network governing alternative carbon metabolism in this organism through characterization of transcriptional regulators identified based on the model fungi, Saccharomyces cerevisiae and Aspergillus nidulans. C. albicans has homologs of the ScCAT8/AnFacB and ScADR1/AnAmdX transcription factors that regulate induction of genes encoding the proteins of gluconeogenesis, the glyoxylate cycle, and ethanol utilization. Surprisingly, C. albicans mutants lacking CAT8 or ADR1 have no apparent phenotypes and do not regulate genes for key enzymes of these pathways. Fatty acid degradation and peroxisomal biogenesis are controlled by nonhomologous regulators, OAF1/PIP2 in S. cerevisiae and FarA/FarB in A. nidulans; C. albicans is missing OAF1 and PIP2 and, instead, has a single homolog of the Far proteins, CTF1. We have shown that CTF1 is required for growth on lipids and for expression of genes necessary for β-oxidation, such as FOX2. ctf1Δ/ctf1Δ (ctf1Δ/Δ) strains do not, however, show the pleiotropic phenotypes observed for fox2Δ/Δ mutants. The ctf1Δ/Δ mutant confers a mild attenuation in virulence, like the fox2Δ/Δ mutant. Thus, phenotypic and genotypic observations highlight important differences in the regulatory network for alternative carbon metabolism in C. albicans compared to the paradigms developed in other model fungi.

scholarly journals Expression of Genes Encoding Innate Host Defense Molecules in Normal Human Monocytes in Response to Candida albicans

2005 ◽  
Vol 73 (6) ◽  
pp. 3714-3724 ◽  
Author(s):  
Hee Sup Kim ◽  
Eun Hwa Choi ◽  
Javed Khan ◽  
Emmanuel Roilides ◽  
Andrea Francesconi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Host Defense ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Human Monocytes ◽  
Potent Inducer ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Normal Human ◽  
Defense Molecules

ABSTRACT Little is known about the regulation and coordinated expression of genes involved in the innate host response to Candida albicans. We therefore examined the kinetic profile of gene expression of innate host defense molecules in normal human monocytes infected with C. albicans using microarray technology. Freshly isolated peripheral blood monocytes from five healthy donors were incubated with C. albicans for 0 to 18 h in parallel with time-matched uninfected control cells. RNA from monocytes was extracted and amplified for microarray analysis, using a 42,421-gene cDNA chip. Expression of genes encoding proinflammatory cytokines, including tumor necrosis factor alpha, interleukin 1 (IL-1), IL-6, and leukemia inhibitory factor, was markedly enhanced during the first 6 h and coincided with an increase in phagocytosis. Expression of these genes returned to near baseline by 18 h. Genes encoding chemokines, including IL-8; macrophage inflammatory proteins 1, 3, and 4; and monocyte chemoattractant protein 1, also were strongly up-regulated, with peak expression at 4 to 6 h, as were genes encoding chemokine receptors CCR1, CCR5, CCR7, and CXCR5. Expression of genes whose products may protect monocyte viability, such as BCL2-related protein, metallothioneins, CD71, and SOCS3, was up-regulated at 4 to 6 h and remained elevated throughout the 18-h time course. On the other hand, expression of genes encoding T-cell-regulatory molecules (e.g., IL-12, gamma interferon, and transforming growth factor β) was not significantly affected during the 18-h incubation. Moreover, genes encoding IL-15, the IL-13 receptor (IL-13Ra1), and CD14 were suppressed during the 18-h exposure to C. albicans. Thus, C. albicans is a potent inducer of a dynamic cascade of expression of genes whose products are related to the recruitment, activation, and protection of neutrophils and monocytes.

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