scholarly journals The Candida albicans TOR-Activating GTPases Gtr1 and Rhb1 Coregulate Starvation Responses and Biofilm Formation

mSphere ◽  
2017 ◽  
Vol 2 (6) ◽  
Author(s):  
Peter R. Flanagan ◽  
Ning-Ning Liu ◽  
Darren J. Fitzpatrick ◽  
Karsten Hokamp ◽  
Julia R. Köhler ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Biofilm Formation ◽  
Nitrogen Starvation ◽  
Antifungal Drugs ◽  
Target Of Rapamycin ◽  
Content Type ◽  
Expression Of Genes ◽  
Wide Range

ABSTRACT Candida albicans is the major fungal pathogen of humans and is responsible for a wide range of infections, including life-threatening systemic infections in susceptible hosts. Target of rapamycin complex 1 (TORC1) is an essential regulator of metabolism in this fungus, and components of this complex are under increased investigation as targets for new antifungal drugs. The present study characterized the role of GTR1, encoding a putative GTPase, in TORC1 activation. This study shows that GTR1 encodes a protein required for activation of TORC1 activity in response to amino acids and regulation of nitrogen starvation responses. GTR1 mutants show increased cell-cell adhesion and biofilm formation and increased expression of genes involved in these processes. This study demonstrates that starvation responses and biofilm formation are coregulated by GTR1 and suggests that these responses are linked to compete with the microbiome for space and nutrients. Target of rapamycin complex 1 (TORC1) is an essential regulator of metabolism in eukaryotic cells and in the fungal pathogen Candida albicans regulates morphogenesis and nitrogen acquisition. Gtr1 encodes a highly conserved GTPase that in Saccharomyces cerevisiae regulates nitrogen sensing and TORC1 activation. Here, we characterize the role of C. albicans GTR1 in TORC1 activation and compare it with the previously characterized GTPase Rhb1. A homozygous gtr1/gtr1 mutant exhibited impaired TORC1-mediated phosphorylation of ribosomal protein S6 and increased susceptibility to rapamycin. Overexpression of GTR1 impaired nitrogen starvation-induced filamentous growth, MEP2 expression, and growth in bovine serum albumin as the sole nitrogen source. Both GTR1 and RHB1 were shown to regulate genes involved in ribosome biogenesis, amino acid biosynthesis, and expression of biofilm growth-induced genes. The rhb1/rhb1 mutant exhibited a different pattern of expression of Sko1-regulated genes and increased susceptibility to Congo red and calcofluor white. The homozygous gtr1/gtr1 mutant exhibited enhanced flocculation phenotypes and, similar to the rhb1/rhb1 mutant, exhibited enhanced biofilm formation on plastic surfaces. In summary, Gtr1 and Rhb1 link nutrient sensing and biofilm formation and this connectivity may have evolved to enhance the competitiveness of C. albicans in niches where there is intense competition with other microbes for space and nutrients. IMPORTANCE Candida albicans is the major fungal pathogen of humans and is responsible for a wide range of infections, including life-threatening systemic infections in susceptible hosts. Target of rapamycin complex 1 (TORC1) is an essential regulator of metabolism in this fungus, and components of this complex are under increased investigation as targets for new antifungal drugs. The present study characterized the role of GTR1, encoding a putative GTPase, in TORC1 activation. This study shows that GTR1 encodes a protein required for activation of TORC1 activity in response to amino acids and regulation of nitrogen starvation responses. GTR1 mutants show increased cell-cell adhesion and biofilm formation and increased expression of genes involved in these processes. This study demonstrates that starvation responses and biofilm formation are coregulated by GTR1 and suggests that these responses are linked to compete with the microbiome for space and nutrients.

scholarly journals The Three Clades of the Telomere-AssociatedTLOGene Family of Candida albicans Have Different Splicing, Localization, and Expression Features

2012 ◽  
Vol 11 (10) ◽  
pp. 1268-1275 ◽  
Author(s):  
Matthew Z. Anderson ◽  
Joshua A. Baller ◽  
Keely Dulmage ◽  
Lauren Wigen ◽  
Judith Berman
Keyword(s):  
Candida Albicans ◽  
Gene Family ◽  
Transcription Regulation ◽  
Family Members ◽  
Gene Products ◽  
Content Type ◽  
Human Host ◽  
Wide Range ◽  
N Terminus

ABSTRACTCandida albicansgrows within a wide range of host niches, and this adaptability enhances its success as a commensal and as a pathogen. The telomere-associatedTLOgene family underwent a recent expansion from one or two copies in other CUG clade members to 14 expressed copies inC. albicans. This correlates with increased virulence and clinical prevalence relative to those of otherCandidaclade species. The 14 expressedTLOgene family members have a conserved Med2 domain at the N terminus, suggesting a role in general transcription. The C-terminal half is more divergent, distinguishing three clades: clade α and clade β have no introns and encode proteins that localize primarily to the nucleus; clade γ sometimes undergoes splicing, and the gene products localize within the mitochondria as well as the nuclei. Additionally,TLOα genes are generally expressed at much higher levels than areTLOγ genes. We propose that expansion of theTLOgene family and the predicted role of Tlo proteins in transcription regulation provideC. albicanswith the ability to adapt rapidly to the broad range of different environmental niches within the human host.

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.

scholarly journals Role of the WOR1 Promoter of Candida albicans in Opaque Commitment

mBio ◽  
2021 ◽  
Author(s):  
Thomas P. Conway ◽  
Kayla Conway ◽  
Frank A. Boksa ◽  
Claude Pujol ◽  
Deborah Wessels ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Gastrointestinal Tract ◽  
Fungal Pathogen ◽  
Lower Gastrointestinal Tract ◽  
Content Type ◽  
Phenotypic Transition

Candida albicans , the most pervasive fungal pathogen colonizing humans, undergoes a phenotypic transition between a white and opaque phenotype. The unique opaque phenotype is necessary for mating and colonization of the lower gastrointestinal tract.

scholarly journals Antifungal effects of alantolactone on Candida albicans: an in vitro study

2021 ◽  
Author(s):  
Xin Liu ◽  
Lili Zhong ◽  
Zhiming Ma ◽  
Yujie Sui ◽  
Jia’nan Xie ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Medical Devices ◽  
Fungal Pathogen ◽  
Biofilm Formation ◽  
In Vitro Study ◽  
Antifungal Drugs ◽  
Promising Candidate ◽  
Human Fungal Pathogen ◽  
Antifungal Effects

AbstractThe human fungal pathogen Candida albicans can cause many kinds of infections, including biofilm infections on medical devices, while the available antifungal drugs are limited to only a few. In this study, alantolactone (Ala) demonstrated antifungal activities against C. albicans, as well as other Candida species, with a MIC of 72 μg/mL. Ala could also inhibit the adhesion, yeast-to-hyphal transition, biofilm formation and development of C. albicans. The exopolysaccharide of biofilm matrix and extracellular phospholipase production could also be reduced by Ala treatment. Ala could increase permeability of C. albicans cell membrane and ROS contribute to the antifungal activity of Ala. Overall, the present study suggests that Ala may provide a promising candidate for developing antifungal drugs against C. albicans infections.

scholarly journals Transcriptomic and Genomic Approaches for Unravelling Candida albicans Biofilm Formation and Drug Resistance—An Update

Genes ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 540 ◽  
Author(s):  
Pei Chong ◽  
Voon Chin ◽  
Won Wong ◽  
Priya Madhavan ◽  
Voon Yong ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Fungal Pathogen ◽  
Biofilm Formation ◽  
Antifungal Drugs ◽  
Yeast Cells ◽  
Whole Genome ◽  
Different Strains

Candida albicans is an opportunistic fungal pathogen, which causes a plethora of superficial, as well as invasive, infections in humans. The ability of this fungus in switching from commensalism to active infection is attributed to its many virulence traits. Biofilm formation is a key process, which allows the fungus to adhere to and proliferate on medically implanted devices as well as host tissue and cause serious life-threatening infections. Biofilms are complex communities of filamentous and yeast cells surrounded by an extracellular matrix that confers an enhanced degree of resistance to antifungal drugs. Moreover, the extensive plasticity of the C. albicans genome has given this versatile fungus the added advantage of microevolution and adaptation to thrive within the unique environmental niches within the host. To combat these challenges in dealing with C. albicans infections, it is imperative that we target specifically the molecular pathways involved in biofilm formation as well as drug resistance. With the advent of the -omics era and whole genome sequencing platforms, novel pathways and genes involved in the pathogenesis of the fungus have been unraveled. Researchers have used a myriad of strategies including transcriptome analysis for C. albicans cells grown in different environments, whole genome sequencing of different strains, functional genomics approaches to identify critical regulatory genes, as well as comparative genomics analysis between C. albicans and its closely related, much less virulent relative, C. dubliniensis, in the quest to increase our understanding of the mechanisms underlying the success of C. albicans as a major fungal pathogen. This review attempts to summarize the most recent advancements in the field of biofilm and antifungal resistance research and offers suggestions for future directions in therapeutics development.

scholarly journals Hog1 Regulates Stress Tolerance and Virulence in the Emerging Fungal PathogenCandida auris

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Alison M. Day ◽  
Megan M. McNiff ◽  
Alessandra da Silva Dantas ◽  
Neil A. R. Gow ◽  
Janet Quinn
Keyword(s):  
Protein Kinase ◽  
Stress Resistance ◽  
Fungal Pathogen ◽  
Antifungal Drugs ◽  
Control Measures ◽  
Emerging Pathogen ◽  
Candida Auris ◽  
Content Type ◽  
Resistance Profile

ABSTRACTCandida aurishas recently emerged as an important, multidrug-resistant fungal pathogen of humans. Comparative studies indicate that despite high levels of genetic divergence,C. aurisis as virulent as the most pathogenic member of the genus,Candida albicans. However, key virulence attributes ofC. albicans, such as morphogenetic switching, are not utilized byC. auris, indicating that this emerging pathogen employs alternative strategies to infect and colonize the host. An important trait required for the pathogenicity of many fungal pathogens is the ability to adapt to host-imposed stresses encountered during infection. Here, we investigated the relative resistance ofC. aurisand other pathogenicCandidaspecies to physiologically relevant stresses and explored the role of the evolutionarily conserved Hog1 stress-activated protein kinase (SAPK) in promoting stress resistance and virulence. In comparison toC. albicans,C. aurisis relatively resistant to hydrogen peroxide, cationic stress, and cell-wall-damaging agents. However, in contrast to otherCandidaspecies examined,C. auris was unable to grow in an anaerobic environment and was acutely sensitive to organic oxidative-stress-inducing agents. An analysis ofC. aurishog1Δ cells revealed multiple roles for this SAPK in stress resistance, cell morphology, aggregation, and virulence. These data demonstrate thatC. aurishas a unique stress resistance profile compared to those of other pathogenicCandidaspecies and that the Hog1 SAPK has pleiotropic roles that promote the virulence of this emerging pathogen.IMPORTANCEThe rapid global emergence and resistance ofCandidaauristo current antifungal drugs highlight the importance of understanding the virulence traits exploited by this human fungal pathogen to cause disease. Here, we characterize the stress resistance profile ofC. aurisand the role of the Hog1 stress-activated protein kinase (SAPK) in stress resistance and virulence. Our findings thatC. aurisis acutely sensitive to certain stresses may facilitate control measures to prevent persistent colonization in hospital settings. Furthermore, our observation that the Hog1 SAPK promotesC. aurisvirulence akin to that reported for many other pathogenic fungi indicates that antifungals targeting Hog1 signaling would be broad acting and effective, even on emerging drug-resistant pathogens.

scholarly journals Roles of the Transcription Factors Sfl2 and Efg1 in White-Opaque Switching in a/α Strains ofCandida albicans

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Yang-Nim Park ◽  
Kayla Conway ◽  
Thomas P. Conway ◽  
Karla J. Daniels ◽  
David R. Soll
Keyword(s):  
Candida Albicans ◽  
Transcription Factors ◽  
Carbon Source ◽  
Environmental Conditions ◽  
Fungal Pathogen ◽  
Type Locus ◽  
Content Type ◽  
Physiological Conditions ◽  
Ofcandida Albicans

ABSTRACTCandida albicansremains the most pervasive fungal pathogen colonizing humans. The majority of isolates from hosts are heterozygous at the mating type locus (MTLa/α), and a third of these have recently been shown to be capable of switching to the opaque phenotype. Here we have investigated the roles of two transcription factors (TFs) Sfl2 and Efg1, in repressing switching ina/α strains. Deleting either gene results in the capacity ofa/α cells to switch to opaque en masse under facilitating environmental conditions, which includeN-acetylglucosamine (GlcNAc) as the carbon source, physiological temperature (37°C), and high CO2(5%). These conditions are similar to those in the host. Our results further reveal that while glucose is a repressor ofsfl2Δ andefg1Δ switching, GlcNAc is an inducer. Finally, we show that when GlcNAc is the carbon source, and the temperature is low (25°C), theefg1Δ mutants, but not thesfl2Δ mutants, form a tiny, elongate cell, which differentiates into an opaque cell when transferred to conditions optimal fora/α switching. These results demonstrate that at least two TFs, Sfl2 and Efg1, repress switching ina/α cells and thata/α strains with either ansfl2Δ orefg1Δ mutation can switch en masse but only under physiological conditions. The role of opaquea/α cells in commensalism and pathogenesis must, therefore, be investigated.IMPORTANCEMore than 95% ofCandida albicansstrains isolated from humans areMTLa/α, and approximately a third of these can undergo the white-to-opaque transition. Therefore, besides being a requirement forMTL-homozygous strains to mate, the opaque phenotype very likely plays a role in the commensalism and pathogenesis of nonmating,a/α populations colonizing humans.

scholarly journals A conserved regulator controls asexual sporulation in the fungal pathogen Candida albicans

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Arturo Hernández-Cervantes ◽  
Sadri Znaidi ◽  
Lasse van Wijlick ◽  
Iryna Denega ◽  
Virginia Basso ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Chromatin Immunoprecipitation ◽  
Fungal Pathogen ◽  
Hyphal Growth ◽  
Second Phase ◽  
Asexual Sporulation ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Genome Wide Expression

AbstractTranscription factor Rme1 is conserved among ascomycetes and regulates meiosis and pseudohyphal growth in Saccharomyces cerevisiae. The genome of the meiosis-defective pathogen Candida albicans encodes an Rme1 homolog that is part of a transcriptional circuitry controlling hyphal growth. Here, we use chromatin immunoprecipitation and genome-wide expression analyses to study a possible role of Rme1 in C. albicans morphogenesis. We find that Rme1 binds upstream and activates the expression of genes that are upregulated during chlamydosporulation, an asexual process leading to formation of large, spherical, thick-walled cells during nutrient starvation. RME1 deletion abolishes chlamydosporulation in three Candida species, whereas its overexpression bypasses the requirement for chlamydosporulation cues and regulators. RME1 expression levels correlate with chlamydosporulation efficiency across clinical isolates. Interestingly, RME1 displays a biphasic pattern of expression, with a first phase independent of Rme1 function and dependent on chlamydospore-inducing cues, and a second phase dependent on Rme1 function and independent of chlamydospore-inducing cues. Our results indicate that Rme1 plays a central role in chlamydospore development in Candida species.

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.

scholarly journals Improved Gene Ontology Annotation for Biofilm Formation, Filamentous Growth, and Phenotypic Switching in Candida albicans

2012 ◽  
Vol 12 (1) ◽  
pp. 101-108 ◽  
Author(s):  
Diane O. Inglis ◽  
Marek S. Skrzypek ◽  
Martha B. Arnaud ◽  
Jonathan Binkley ◽  
Prachi Shah ◽  
...  
Keyword(s):  
Gene Ontology ◽  
Candida Albicans ◽  
Gene Product ◽  
Fungal Pathogen ◽  
Biofilm Formation ◽  
Filamentous Growth ◽  
Phenotypic Switching ◽  
Gene Products ◽  
Content Type ◽  
Opportunistic Fungal Pathogen

ABSTRACTThe opportunistic fungal pathogenCandida albicansis a significant medical threat, especially for immunocompromised patients. Experimental research has focused on specific areas ofC. albicansbiology, with the goal of understanding the multiple factors that contribute to its pathogenic potential. Some of these factors include cell adhesion, invasive or filamentous growth, and the formation of drug-resistant biofilms. The Gene Ontology (GO) (www.geneontology.org) is a standardized vocabulary that theCandidaGenome Database (CGD) (www.candidagenome.org) and other groups use to describe the functions of gene products. To improve the breadth and accuracy of pathogenicity-related gene product descriptions and to facilitate the description of as yet uncharacterized but potentially pathogenicity-related genes inCandidaspecies, CGD undertook a three-part project: first, the addition of terms to the biological process branch of the GO to improve the description of fungus-related processes; second, manual recuration of gene product annotations in CGD to use the improved GO vocabulary; and third, computational ortholog-based transfer of GO annotations from experimentally characterized gene products, using these new terms, to uncharacterized orthologs in otherCandidaspecies. Through genome annotation and analysis, we identified candidate pathogenicity genes in seven non-C. albicans Candidaspecies and in one additionalC. albicansstrain, WO-1. We also defined a set ofC. albicansgenes at the intersection of biofilm formation, filamentous growth, pathogenesis, and phenotypic switching of this opportunistic fungal pathogen, which provides a compelling list of candidates for further experimentation.

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