Gcn5 Controls Virulence of the Human Fungal Pathogen Candida albicans through Multiple Regulatory Networks
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ABSTRACT:
ORGANISM(S): Candida albicans
PROVIDER: GSE123412 | GEO | 2019/07/26
REPOSITORIES: GEO
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Project description:Gcn5 Controls Virulence of the Human Fungal Pathogen Candida albicans through Multiple Regulatory Networks
| PRJNA508646 | ENA
Project description:Fungal virulence is regulated by a tight interplay of transcriptional control and chromatin remodelling. Despite compelling evidence that lysine acetylation modulates virulence of pathogenic fungi such as Candida albicans, the underlying mechanisms have remained largely unexplored. We report here that Gcn5, a paradigm lysyl-acetyl transferase (KAT) modifying both histone and non-histone targets, controls fungal morphogenesis - a key virulence factor of C. albicans. Our data show that genetic removal of GCN5 abrogates fungal virulence in mice, suggesting strongly diminished fungal fitness in vivo. This may at least in part arise from increased susceptibility to killing by macrophages, as well as by other phagocytes such as neutrophils or monocytes. Loss of GCN5 also causes hypersensitivity to the fungicidal drug caspofungin. Caspofungin hypersusceptibility requires the master regulator Efg1, working in concert with Gcn5. Moreover, Gcn5 regulates multiple independent pathways, including adhesion, cell wall-mediated MAP kinase signaling, hypersensitivity to host-derived oxidative stress, and regulation of the Fks1 glucan synthase, all of which play critical roles in virulence and antifungal susceptibility. Hence, Gcn5 regulates fungal virulence through multiple mechanisms, suggesting that specific inhibition of Gcn5 could offer new therapeutic strategies to combat invasive fungal infections.
| S-EPMC6603162 | biostudies-literature
Project description:Inside the human host, the pathogenic yeast Candida albicans colonizes predominantly oxygen-poor niches such as the gastrointestinal and vaginal tracts, but also oxygen-rich environments such as cutaneous epithelial cells and oral mucosa. This suppleness requires an effective mechanism to reprogram reversibly the primary metabolism in response to oxygen variation. Here, we have uncovered that Snf5, a subunit of SWI/SNF chromatin remodeling complex, is a major transcriptional regulator that links oxygen status to the metabolic capacity of C. albicans. Snf5 and other subunits of SWI/SNF complex were required to activate genes of carbon utilization and other carbohydrates related process specifically under hypoxia. snf5 mutant exhibited an altered metabolome reflecting that SWI/SNF plays an essential role in maintaining metabolic homeostasis and carbon flux in C. albicans under hypoxia. Snf5 was necessary to activate the transcriptional program linked to both commensal and invasive growth. Accordingly, snf5 was unable to maintain its growth in the stomach, the cecum and the colon of mice. snf5 was also avirulent as it was unable to invade Galleria larvae or to cause damage to human enterocytes and murine macrophages. Among candidates of signaling pathways in which Snf5 might operate, phenotypic analysis revealed that mutants of Ras1-cAMP-PKA pathway, as well as mutants of Yak1 and Yck2 kinases exhibited a similar carbon flexibility phenotype as did snf5 under hypoxia. Genetic interaction analysis indicated that the adenylate cyclase Cyr1, a key component of the Ras1-cAMP pathway genetically with Snf5. Our study yielded new insight into the oxygen-sensitive regulatory circuit that control metabolic flexibility, stress, commensalism and virulence in C. albicans.
2019-09-19 | GSE137655 | GEO
Project description:Expression profiles of five caspofungin adapted candida albicans strains were analysed from their parental strains
2022-11-05 | GSE217094 | GEO
Project description:At human body temperature, the fungal pathogen Candida albicans can transition from yeast to filamentous morphologies in response to host-relevant cues. Additionally, elevated temperatures encountered during febrile episodes can independently induce C. albicans filamentation. However, the underlying genetic pathways governing this developmental transition in response to elevated temperature remain largely unexplored. Here, we conducted a functional genomic screen to unravel the genetic mechanisms orchestrating C. albicans filamentation specifically in response to elevated temperature, implicating 45% of genes associated with the spliceosome or pre-mRNA splicing in this process. Employing RNA-Seq to elucidate the relationship between mRNA splicing and filamentation, we identified greater levels of intron retention in filaments compared to yeast, which correlated with reduced expression of the affected genes. Intriguingly, homozygous deletion of a gene encoding a spliceosome component important for filamentation (PRP19) caused even greater levels of intron retention compared with wild-type and globally dysregulated gene expression. This suggests that intron retention is a mechanism for fine-tuning gene expression during filamentation, with perturbations of the spliceosome exacerbating this process and blocking filamentation. Overall, this study unveils a novel biological process governing C. albicans filamentation, providing new insights into the complex regulation of this key virulence trait.
2024-05-28 | GSE262764 | GEO
Project description:So far, there is no known regulatory circuits that mediate filamentation of the pathogenic yeast Candida albicans exclusively in response to hypoxia. In this study, we performed a quantitative analysis of gene deletion mutants from different collections of protein kinases and transcriptional regulators to identify specific regulator of the hypoxic filamentation. Our work uncovered two transcription factors, Ahr1 and Tye7, that act as prominent regulators of C. albicans filamentation specifically under hypoxia. In summary, we used genome-wide transcriptional profiling and promoter occupancy to characterize both Ahr1 and Tye7 regulons associated with the hypoxic filamentation in C. albicans.
2021-08-18 | E-MTAB-10882 | biostudies-arrayexpress
Project description:RNA-seq analysis of Caspofungin sensitive gene expression in Candida albicans.
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Project description:As transition metal availability is very limited inside the human host, fungal pathogens have evolved sophisticated mechanisms to uptake and utilize these micronutrients at the infection interface. While considerable attention was turned into iron, copper and zinc acquisition mechanisms and their importance in fungal fitness, less was done regarding either the role of Mn in infectious processes or the cellular mechanism by which fungal cells achieve their Mn-homeostasis. Here, we undertook a transcriptional profiling of the pathogenic fungus Candida albicans experiencing both Mn starvation and excess to comprehensibly capture biological processes that are modulated by Mn. We uncovered that Mn scarcity influence diverse biological processes associated with fungal fitness including morphogenetic switch, invasion of host cells and antifungal sensitivity. We also uncovered that Mn levels influence the abundance of iron and zinc emphasizing the complex crosstalk between ions metals. Deletion of SMF12, a member of Mn Nramp transporters confirmed its contribution to Mn uptake. In accordance with the RNA-seq data, smf12 was unable to form hyphae and damage host cells, and exhibited sensitivity to azole antifungals. We also found that unfolded protein response (UPR), likely activated by decreased glycosylation under Mn limitation, was essential to promote C. albicans growth. RNA-seq profiling of cells exposed to Mn excess uncovered that the UPR signaling was also essential to bypass Mn toxicity. Collectively, this study underscores the importance of Mn homeostasis in fungal virulence, and comprehensively provides a transcriptional portrait of biological functions that are modulated by Mn in a fungal pathogen.
2024-02-13 | GSE245114 | GEO
Project description:Approximately 200 cells of Candida albicans lab strain SC5314 were spread on YPD plates supplemented with 2 fold increase from 50 ng/ml to 12800ng/ml caspofungin. All adaptors appeared were collected. Randomly 36 tolerant adaptors were sequenced.
2023-09-15 | E-MTAB-12336 | biostudies-arrayexpress
Project description:Comparison of Candida albicans SC5314 treated with fludioxonil for 30 min and untreated controls under hyphae-inducing conditions
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