Transcriptional Control of Hypoxic Hyphal Growth in the Fungal Pathogen Candida albicans

Henry, Manon; Burgain, Anaïs; Tebbji, Faïza; Sellam, Adnane

doi:10.3389/fcimb.2021.770478

Cited by 10 publications

(6 citation statements)

References 60 publications

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“…The expression of Irf1-regulated positive hyphal regulators EFG1, AHR1, TEC1 and BRG1 is also activated under iron deficiency conditions, particularly for EFG1 and BRG1 (Figure 6A). We were able to exclude the involvement of Ahr1 and Tec1 in iron deficiency-induced filamentation, consistently with recently published results on AHR1 (Henry et al, 2021). In contrast, both the efg1-and brg1mutants showed a defect in their ability to form hyphae under iron deficiency (Figure 6C, Hameed et al, 2008).…”

Section: Discussionsupporting

confidence: 91%

Functional Portrait of Irf1 (Orf19.217), a Regulator of Morphogenesis and Iron Homeostasis in Candida albicans

Wijlick

Znaidi²,

Hernández‐Cervantes³

et al. 2022

Front. Cell. Infect. Microbiol.

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The alternate growth of Candida albicans between a unicellular yeast form and a multicellular hyphal form is crucial for its ability to cause disease. Interestingly, both morphological forms support distinct functions during proliferation in the human host. We previously identified ORF19.217 (C2_08890W_A), encoding a zinc-finger transcription factor of the C2H2 family, in a systematic screen of genes whose overexpression contributes to C. albicans’ morphological changes. Conditional overexpression of ORF19.217 with the strong tetracycline-inducible promoter (PTET) resulted in a hyperfilamentous phenotype. We examined growth of the orf19.217 knockout-mutant in different hypha-inducing conditions and found that the mutant still formed hyphae under standard hypha-inducing conditions. To further investigate the function of Orf19.217 in C. albicans, we combined genome-wide expression (RNA-Seq) and location (ChIP-Seq) analyses. We found that Orf19.217 is involved in regulatory processes comprising hyphal morphogenesis and iron acquisition. Comparative analysis with existing C. albicans hyphal transcriptomes indicates that Orf19.217-mediated filamentation is distinct from a true hyphal program. Further, the orf19.217 knockout-mutant did not show increased sensitivity to iron deprivation, but ORF19.217 overexpression was able to rescue the growth of a hap5-mutant, defective in a subunit of the CCAAT-complex, which is essential for iron acquisition. This suggested that Orf19.217 is involved in regulation of iron acquisition genes during iron deprivation and acts in a parallel pathway to the established CCAAT-complex. Interestingly, the orf19.217-mutant turned out to be defective in its ability to form filaments under iron-deficiency. Taken together our findings propose that the transcription factor Orf19.217 stimulates expression of the hyphal regulators EFG1 and BRG1 to promote filamentous growth under iron deprivation conditions, allowing the fungus to escape these iron-depleted conditions. The transcription factor therefore appears to be particularly important for adaptation of C. albicans to diverse environmental conditions in the human host. In regard to the newly identified functions, we have given the regulator the name Irf1, Iron-dependent Regulator of Filamentation.

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Section: Discussionsupporting

confidence: 91%

Functional Portrait of Irf1 (Orf19.217), a Regulator of Morphogenesis and Iron Homeostasis in Candida albicans

Wijlick

Znaidi²,

Hernández‐Cervantes³

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Furthermore, it acts as a negative regulator of hypoxic filamentation (36). Despite the overexpression of TYE7, several key genes in glycolysis were significantly down-regulated (PGI1, PFK1, PFK2, TPI1, TDH3, GPM1, ENO1), especially under tyrosol exposure.…”

Section: Discussionmentioning

confidence: 99%

Comparative transcriptional analysis ofCandida aurisbiofilms following farnesol and tyrosol treatment

Jakab,

Kovács,

Balla

et al. 2023

Preprint

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Candida aurisis frequently associated with biofilm-related invasive infections. The resistant profile of these biofilms necessitates innovative therapeutic options, where quorum sensing may be a potential target. Farnesol and tyrosol are two fungal quorum-sensing molecules with antifungal effects at supraphysiological concentrations. To date there has been no high-throughput comparative molecular analysis regarding the background of farnesol– or tyrosol-related effects againstC. aurisbiofilms. Here, we performed genome-wide transcript profiling withC. aurisbiofilms following 75 μM farnesol or 15 mM tyrosol exposure using transcriptome sequencing (RNA-Seq). The analysis highlighted that the number of up-regulated genes (a minimum 1.5-fold increase) was 686 and 138 for tyrosol and farnesol, respectively, while 662 and 199 genes were down-regulated (a minimum 1.5-fold decrease) for tyrosol and farnesol, respectively. The overlap between tyrosol– and farnesol-responsive genes was considerable (101 and 116 overlapping up-regulated and down-regulated genes, respectively). Genes involved in biofilm events, glycolysis, ergosterol biosynthesis, fatty acid oxidation, iron metabolism, and autophagy were primarily affected in treated cells. Farnesol caused an 89.9%, 73.8%, and 32.6% reduction in the calcium, magnesium, and iron content, respectively, whereas tyrosol resulted an 82.6%, 76.6%, and 81.2% decrease in the calcium, magnesium, and iron content compared to the control, respectively. Moreover, the complexation of farnesol, but not tyrosol, with ergosterol is impeded in the presence of exogenous ergosterol, resulting in a minimum inhibitory concentration increase in the quorum-sensing molecules. This study revealed several farnesol– and tyrosol-specific responses, which will contribute to the development of alternative therapies againstC. aurisbiofilms.ImportanceCandida aurisis a multidrug-resistant fungal pathogen, which is frequently associated with biofilm related infections.Candida-derived quorum-sensing molecules (farnesol and tyrosol) play a pivotal role in the regulation of fungal morphogenesis and biofilm development. Furthermore, they may have remarkable anti-biofilm effects, especially at supraphysiological concentrations. Innovative therapeutic approaches interfering with quorum-sensing may be a promising future strategy againstC. aurisbiofilms; however, limited data are currently available concerning farnesol-induced and tyrosol-related molecular effects inC. auris. Here, we detected several genes involved in biofilm events, glycolysis, ergosterol biosynthesis, fatty acid oxidation, iron metabolism, and autophagy, which were primarily influenced following farnesol or tyrosol exposure. Moreover, calcium, magnesium, and iron homeostasis were also significantly affected. These results reveal molecular events that provide definitive explanations for the observed anti-biofilm effect; furthermore, they support the development of novel therapeutic approaches againstC. aurisbiofilms.

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“…The role of Snf5 in low-oxygen conditions appears to be through interaction with the adenylate cyclase Cyr1 to regulate metabolic flexibility through the Ras-cAMP-protein kinase A (PKA) pathway that is further discussed below (16). Tye7 was also recently identified in another genetic screen as a negative regulator of hyphal growth in low-oxygen conditions along with the transcription factor Ahr1 (61). These transcription factors have been previously described as being involved in carbon metabolism (Tye7) and expression of adhesins (4,5,111).…”

Section: Oxygen and Fungal Disease Progression: Fungal Morphogenesis ...mentioning

confidence: 99%

“…The null mutants tye7 and ahr1 were hyperfilamentous, specifically in the presence of 1% O 2 . Through epistatic analysis it was discovered that Tye7 and Ahr1 act independently in two separate pathways, the Ras1/Cyr1 cAMP pathway and the Efg1 pathway, respectively (61). The ahr1 mutant had a transcriptional profile indicating iron starvation, thus possibly the hyperfilamentation phenotype is for environment exploration and nutrient uptake.…”

Section: Oxygen and Fungal Disease Progression: Fungal Morphogenesis ...mentioning

confidence: 99%

“…This work links biofilm formation to metabolism, specifically glycolysis in the context of Tye7. Given the finding that Ahr1 works in opposition to Tye7 through Efg1 regulation, it is worth noting that positive autoregulation of Efg1 and through Ifu5 is important for the formation of biofilms under hypoxic conditions (61,104,116). Moreover, in C. albicans, SREBPs have been repurposed for gene activation of hypoxia-responsive genes but do not regulate ergosterol biosynthesis, as this is controlled by the Upc2 transcription factor in this organism (88,131).…”

Section: Fungal Biofilms-low-oxygen Niche Specialization and Antifung...mentioning

confidence: 99%

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Recent Advances in Understanding the Human Fungal Pathogen Hypoxia Response in Disease Progression

Puerner,

Vellanki,

Strauch

et al. 2023

Annu. Rev. Microbiol.

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Fungal-mediated disease progression and antifungal drug efficacy are significantly impacted by the dynamic infection microenvironment. At the site of infection, oxygen often becomes limiting and induces a hypoxia response in both the fungal pathogen and host cells. The fungal hypoxia response impacts several important aspects of fungal biology that contribute to pathogenesis, virulence, antifungal drug susceptibility, and ultimately infection outcomes. In this review, we summarize recent advances in understanding the molecular mechanisms of the hypoxia response in the most common human fungal pathogens, discuss potential therapeutic opportunities, and highlight important areas for future research.

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Transcriptional Control of Hypoxic Hyphal Growth in the Fungal Pathogen Candida albicans

Cited by 10 publications

References 60 publications

Functional Portrait of Irf1 (Orf19.217), a Regulator of Morphogenesis and Iron Homeostasis in Candida albicans

Functional Portrait of Irf1 (Orf19.217), a Regulator of Morphogenesis and Iron Homeostasis in Candida albicans

Comparative transcriptional analysis ofCandida aurisbiofilms following farnesol and tyrosol treatment

Recent Advances in Understanding the Human Fungal Pathogen Hypoxia Response in Disease Progression

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