scholarly journals Transcriptional control of hypoxic hyphal growth in the fungal pathogen Candida albicans

2021 ◽  
Author(s):  
Henry Manon ◽  
Anais Burgain ◽  
Faiza Tebbji ◽  
Adnane Sellam
Keyword(s):  
Candida Albicans ◽  
Transcription Factors ◽  
Fungal Pathogen ◽  
Transcriptional Control ◽  
Genetic Interaction ◽  
Transcriptional Profiling ◽  
Hyphal Growth ◽  
Negative Regulator ◽  
Functional Relationships ◽  
Chip Chip

Background: The ability of Candida albicans, an important human fungal pathogen, to develop filamentous forms is a crucial determinant for host invasion and virulence. Filamentation is triggered by different host environmental cues such as temperature and pH. Hypoxia, the dominant conditions that C. albicans encounters inside the human host, promote filamentation, however, the contributing mechanisms remain poorly characterized. Methods: We performed a quantitative analysis of gene deletion mutants from different collections of protein kinases and transcriptional regulators in C. albicans to identify specific modulators of the hypoxic filamentation. We used genome-wide transcriptional profiling (Microarrays) and promoter occupancy (ChIP-chip) to characterize regulons of two transcription factors that were associated with the hypoxic filamentation. Genetic interactions were also used to assess functional relationships among the newly identified modulators of hypoxic filamentation and the well-known C. albicans core morphogenetic regulators. Results: Our genetic screen uncovered two transcription factors, Ahr1 and Tye7, that act as prominent regulators of C. albicans filamentation specifically under hypoxia. Both ahr1 and tye7 mutants exhibited a hyperfilamentous phenotype specifically under an oxygen-depleted environment suggesting that these transcription factors act as a negative regulator of hypoxic filamentation. By combining microarray and ChIP-chip data, we have characterized the set of genes that are directly modulated by Ahr1 and Tye7. We found that both Ahr1 and Tye7 modulate a different set of genes and biological processes. Our genetic epistasis analysis supports our genomic finding and suggests that Ahr1 and Tye7 act independently to modulate hyphal growth in response to hypoxia. Furthermore, our genetic interaction experiments uncovered that Ahr1 and Tye7 repress the hypoxic filamentation growth via the Efg1 and Ras1/Cyr1 pathways, respectively. Conclusion: In sum, this investigation represents an informative resource toward the understanding of how hypoxia, the predominant condition inside the host, shapes the invasive filamentous growth of C. albicans.

scholarly journals The zinc cluster transcription factor Rha1 is a positive filamentation regulator in Candida albicans

2020 ◽  
Author(s):  
Raha Parvizi Omran ◽  
Chris Law ◽  
Vanessa Dumeaux ◽  
Joachim Morschhäuser ◽  
Malcolm Whiteway
Keyword(s):  
Cell Wall ◽  
Transcription Factor ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Transcriptional Profiling ◽  
Hyphal Growth ◽  
Growth Conditions ◽  
Hyphal Development ◽  
Zinc Cluster ◽  
Genes Encoding

AbstractZinc cluster transcription factors are essential fungal specific regulators of gene expression. In the dimorphic pathogen Candida albicans, they control processes ranging from metabolism and stress adaptation to mating, virulence, and antifungal resistance. Here, we have identified the gene CaORF19.1604 as encoding a zinc cluster transcription factor that acts as a regulator of filament development. Hyperactivation of CaORF19.1604, which we have named RHA1 for Regulator of Hyphal Activity, leads to a wrinkled colony morphology under non-hyphal growth conditions, to pseudohyphal growth and filament formation, to invasiveness and enhanced biofilm formation.  Cells with activated Rha1 are sensitive to cell wall modifying agents such as Congo red and the echinocandin drug caspofungin but show normal sensitivity to fluconazole. RNA-sequencing-based transcriptional profiling of the activated Rha1 strain reveals the up-regulation of genes for core filamentation and cell-wall-adhesion-related proteins such as Als1, Als3, Ece1, and Hwp1. Upregulation is also seen for the genes for the hyphal-inducing transcription factors Brg1 and Ume6 and genes encoding several enzymes involved in arginine metabolism, while downregulation is seen for the hyphal repressor Nrg1. The deletion of BRG1 blocks the filamentation caused by activated Rha1, while null mutants of UME6 result in a partial block. Deletion of RHA1 can partially reduce healthy hyphal development triggered by environmental conditions such as Spider medium or serum at 37°C.In contrast to the limited effect of either single mutant, the double rha1 ume6 deletion strain is totally defective in both serum and Spider medium stimulated hyphal development. While the loss of Brg1 function blocks serum-stimulated hyphal development, this block can be significantly bypassed by Rha1 hyperactivity, and the combination of Rha1 hyperactivity and serum addition can generate significant polarization in even brg1 ume6 double mutants. Our results thus suggest that in response to external signals, Rha1 functions to facilitate the switch from an Nrg1 controlled yeast state to a Brg1/Ume6 regulated hyphal state.Author SummaryCandida albicans is the predominant human fungal pathogen, generating a mortality rate of 40% in systemically infected patients. The ability of Candida albicans to change its morphology is a determinant of its tissue penetration and invasion in response to variant host-related stimuli. The regulatory mechanism for filamentation includes a complex network of transcription factors that play roles in regulating hyphae associated genes. We identify here a new regulator of filamentation from the zinc cluster transcription factor family. We present evidence suggesting that this transcription factor assists the Nrg1/Brg1 switch regulating hyphal development.

scholarly journals Role for the SCFCDC4Ubiquitin Ligase inCandida albicansMorphogenesis

2005 ◽  
Vol 16 (6) ◽  
pp. 2772-2785 ◽  
Author(s):  
Avigail Atir-Lande ◽  
Tsvia Gildor ◽  
Daniel Kornitzer
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Ubiquitin Ligase ◽  
Fungal Pathogen ◽  
Ectopic Expression ◽  
Hyphal Growth ◽  
Yeast Form ◽  
Epistasis Analysis ◽  
F Box Protein

The ability of Candida albicans, a major fungal pathogen, to switch between a yeast form, and a hyphal (mold) form is recognized as being important for the ability of the organism to invade the host and cause disease. We found that a C. albicans mutant deleted for CaCDC4, a homologue of the Saccharomyces cerevisiae F-box protein component of the SCFCDC4ubiquitin ligase, is viable and displays constitutive filamentous, mostly hyphal, growth. The phenotype of the Cacdc4–/– mutant suggests that ubiquitin-mediated protein degradation is involved in the regulation of the dimorphic switch of C. albicans and that one or more regulators of the yeast-to-mold switch are among the substrates of SCFCaCDC4. Epistasis analysis indicates that the Cacdc4–/– phenotype is largely independent of the filamentation-inducing transcription factors Efg1 and Cph1. We identify C. albicans Far1 and Sol1, homologues of the S. cerevisiae SCFCDC4substrates Far1 and Sic1, and show that Sol1 is a substrate of C. albicans Cdc4. Neither protein is essential for the hyphal phenotype of the Cacdc4–/– mutant. However, ectopic expression and deletion of SOL1 indicate a role for this gene in C. albicans morphogenesis.

scholarly journals Candida albicans Transcriptional Profiling Within Biliary Fluid From a Patient With Cholangitis, Before and After Antifungal Treatment and Surgical Drainage

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Cornelius J. Clancy ◽  
Camille Meslin ◽  
Hassan Badrane ◽  
Shaoji Cheng ◽  
Liliana C. Losada ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Transcriptional Profiling ◽  
Hyphal Growth ◽  
Global Gene Expression ◽  
Human Infection ◽  
Ergosterol Biosynthesis ◽  
Infection Site ◽  
Oxidation Reduction ◽  
Cell Wall Organization ◽  
Before And After

Abstract We used ribonucleic acid sequencing to profile Candida albicans transcription within biliary fluid from a patient with cholangitis; samples were collected before and after treatment with fluconazole and drainage. Candida albicans transcriptomes at the infection site distinguished treated from untreated cholangitis. After treatment, 1131 C. albicans genes were differentially expressed in biliary fluid. Up-regulated genes were enriched in hyphal growth, cell wall organization, adhesion, oxidation reduction, biofilm, and fatty acid and ergosterol biosynthesis. This is the first study to define Candida global gene expression during deep-seated human infection. Successful treatment of cholangitis induced C. albicans genes involved in fluconazole responses and pathogenesis.

scholarly journals Cdc24, the GDP-GTP Exchange Factor for Cdc42, Is Required for Invasive Hyphal Growth of Candida albicans

2003 ◽  
Vol 2 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Martine Bassilana ◽  
James Blyth ◽  
Robert A. Arkowitz
Keyword(s):  
Candida Albicans ◽  
Protein Kinase ◽  
G Protein ◽  
Fungal Pathogen ◽  
Ectopic Expression ◽  
Hyphal Growth ◽  
Mitogen Activated Protein Kinase ◽  
Filamentous Form ◽  
Exchange Factor ◽  
Polarity Establishment

ABSTRACT Candida albicans, the most common human fungal pathogen, is particularly problematic for immunocompromised individuals. The reversible transition of this fungal pathogen to a filamentous form that invades host tissue is important for its virulence. Although different signaling pathways such as a mitogen-activated protein kinase and a protein kinase A cascade are critical for this morphological transition, the function of polarity establishment proteins in this process has not been determined. We examined the role of four different polarity establishment proteins in C. albicans invasive growth and virulence by using strains in which one copy of each gene was deleted and the other copy expressed behind the regulatable promoter MET3. Strikingly, mutants with ectopic expression of either the Rho G-protein Cdc42 or its exchange factor Cdc24 are unable to form invasive hyphal filaments and germ tubes in response to serum or elevated temperature and yet grow normally as a budding yeast. Furthermore, these mutants are avirulent in a mouse model for systemic infection. This function of the Cdc42 GTPase module is not simply a general feature of polarity establishment proteins. Mutants with ectopic expression of the SH3 domain containing protein Bem1 or the Ras-like G-protein Bud1 can grow in an invasive fashion and are virulent in mice, albeit with reduced efficiency. These results indicate that a specific regulation of Cdc24/Cdc42 activity is required for invasive hyphal growth and suggest that these proteins are required for pathogenicity of C. albicans.

scholarly journals Conjugated Linoleic Acid Inhibits Hyphal Growth in Candida albicans by Modulating Ras1p Cellular Levels and Downregulating TEC1 Expression

2011 ◽  
Vol 10 (4) ◽  
pp. 565-577 ◽  
Author(s):  
Julie Shareck ◽  
André Nantel ◽  
Pierre Belhumeur
Keyword(s):  
Candida Albicans ◽  
Linoleic Acid ◽  
Conjugated Linoleic Acid ◽  
Cellular Localization ◽  
Therapeutic Potential ◽  
Transcriptional Profiling ◽  
Hyphal Growth ◽  
Cellular Growth ◽  
Content Type ◽  
Protein Levels

ABSTRACTThe polymorphic yeastCandida albicansexists in yeast and filamentous forms. Given that the morphogenetic switch coincides with the expression of many virulence factors, the yeast-to-hypha transition constitutes an attractive target for the development of new antifungal agents. Since an untapped therapeutic potential resides in small molecules that hinderC. albicansfilamentation, we characterized the inhibitory effect of conjugated linoleic acid (CLA) on hyphal growth and addressed its mechanism of action. CLA inhibited hyphal growth in a dose-dependent fashion in both liquid and solid hypha-inducing media. The fatty acid blocked germ tube formation without affecting cellular growth rates. Global transcriptional profiling revealed that CLA downregulated the expression of hypha-specific genes and abrogated the induction of several regulators of hyphal growth, includingTEC1,UME6,RFG1, andRAS1. However, neitherUME6norRFG1was necessary for CLA-mediated hyphal growth inhibition. Expression analysis showed that the downregulation ofTEC1expression levels by CLA depended onRAS1. In addition, whileRAS1transcript levels remained constant in CLA-treated cells, its protein levels declined with time. With the use of a strain expressing GFP-Ras1p, CLA treatment was also shown to affect Ras1p localization to the plasma membrane. These findings suggest that CLA inhibits hyphal growth by affecting the cellular localization of Ras1p and blocking the increase inRAS1mRNA and protein levels. Combined, these effects should prevent the induction of the Ras1p signaling pathway. This study provides the biological and molecular explanations that underlie CLA's ability to inhibit hyphal growth inC. albicans.

Design, execution, and analysis of CRISPR–Cas9-based deletions and genetic interaction networks in the fungal pathogen Candida albicans

2019 ◽  
Vol 14 (3) ◽  
pp. 955-975 ◽  
Author(s):  
Viola Halder ◽  
Caroline B. M. Porter ◽  
Alejandro Chavez ◽  
Rebecca S. Shapiro
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Genetic Interaction ◽  
Interaction Networks

scholarly journals Drosophila melanogaster Thor and Response to Candida albicans Infection

2007 ◽  
Vol 6 (4) ◽  
pp. 658-663 ◽  
Author(s):  
A. Levitin ◽  
A. Marcil ◽  
G. Tettweiler ◽  
M. J. Laforest ◽  
U. Oberholzer ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Drosophila Melanogaster ◽  
Candida Albicans ◽  
Host Defense ◽  
Translational Control ◽  
Fungal Pathogen ◽  
Transcriptional Profiling ◽  
S2 Cells ◽  
Candida Albicans Infection ◽  
Opportunistic Fungal Pathogen

ABSTRACT We used Drosophila melanogaster macrophage-like Schneider 2 (S2) cells as a model to study cell-mediated innate immunity against infection by the opportunistic fungal pathogen Candida albicans. Transcriptional profiling of S2 cells coincubated with C. albicans cells revealed up-regulation of several genes. One of the most highly up-regulated genes during this interaction is the D. melanogaster translational regulator 4E-BP encoded by the Thor gene. Analysis of Drosophila 4E-BP null mutant survival upon infection with C. albicans showed that 4E-BP plays an important role in host defense, suggesting a role for translational control in the D. melanogaster response to C. albicans infection.

scholarly journals High Resistance to Oxidative Stress in the Fungal Pathogen Candida glabrata Is Mediated by a Single Catalase, Cta1p, and Is Controlled by the Transcription Factors Yap1p, Skn7p, Msn2p, and Msn4p

2008 ◽  
Vol 7 (5) ◽  
pp. 814-825 ◽  
Author(s):  
Mayra Cuéllar-Cruz ◽  
Marcela Briones-Martin-del-Campo ◽  
Israel Cañas-Villamar ◽  
Javier Montalvo-Arredondo ◽  
Lina Riego-Ruiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Adaptive Response ◽  
Fungal Pathogen ◽  
Candida Glabrata ◽  
Systemic Infection ◽  
Oxidative Stress Response

ABSTRACT We characterized the oxidative stress response of Candida glabrata to better understand the virulence of this fungal pathogen. C. glabrata could withstand higher concentrations of H2O2 than Saccharomyces cerevisiae and even Candida albicans. Stationary-phase cells were extremely resistant to oxidative stress, and this resistance was dependent on the concerted roles of stress-related transcription factors Yap1p, Skn7p, and Msn4p. We showed that growing cells of C. glabrata were able to adapt to high levels of H2O2 and that this adaptive response was dependent on Yap1p and Skn7p and partially on the general stress transcription factors Msn2p and Msn4p. C. glabrata has a single catalase gene, CTA1, which was absolutely required for resistance to H2O2 in vitro. However, in a mouse model of systemic infection, a strain lacking CTA1 showed no effect on virulence.

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.

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