Gcn5 Controls Virulence of the Human Fungal Pathogen Candida albicans through Multiple Regulatory Networks
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PROVIDER: PRJNA508646 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptomic analysis of wild type and GCN5-deficient Candida albicans cells prior to and after treatment with Caspofungin 15 min and 45 min was done to determine the transcriptional changes in these strains
2019-07-26 | GSE123412 | GEO
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
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| S-EPMC6603162 | biostudies-literature
Project description:C. albicans glucose sensing and signaling is important for full virulence in the mammalian host. To better understand this phenomenon, we investigated the Hgt4 glucose-sensing pathway, focusing on the downstream transcriptional repressor CaRgt1. CaRgt1-regulated gene transcripts were identified by comparing total RNA extracted from wild type and rgt1 mutant strains. Cells were grown at 37 degrees C in the presence of glycerol, conditions under which CaRgt1 was expected to repress gene transcription. Keywords: cell type comparison
2007-03-01 | GSE7044 | GEO
Project description:C. albicans glucose sensing and signaling is important for full virulence in the mammalian host. To better understand this phenomenon, we investigated the Hgt4 glucose-sensing pathway, focusing on the downstream transcriptional repressor CaRgt1. CaRgt1-regulated gene transcripts were identified by comparing total RNA extracted from wild type and rgt1 mutant strains. Cells were grown at 30 degrees C in the presence of glycerol, conditions under which CaRgt1 was expected to repress gene transcription. Keywords: cell type comparison
2007-03-01 | GSE7043 | GEO
Project description:Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity. Here, we compare the acetylomes of baker’s yeast and the three deadliest human fungal pathogens, Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Using mass spectrometry enriched for acetylated peptides together with public data from Saccharomyces cerevisiae, we show that fungal acetylomes are characterized by dramatic evolutionary dynamics and limited conservation in core biological processes. Notably, the levels of protein acetylation in pathogenic fungi correlate with their pathogenicity. Using gene knockouts and pathogenity assays in mice, we identify deacetylases with critical roles in virulence and protein translation elongation. Finally, through mutational analysis of deactylation motifs we find evidence of positive selection at specific acetylation motifs in fungal pathogens. These results shed new light on the pathogenicity regulation mechanisms underlying the evolution of fungal acetylomes.
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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: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:The interaction between fungal pathogen and host during infection is a complex and dynamic process. To resolve this, we chose the zebrafish model organism as the host to study C. albicans infection via systems biology approach. Transcriptome microarray data and histological analysis of surviving fish were sampled at different post-infection time points. The dynamic variations of significant genes expression profiles in C. albicans and zebrafish were concurrently analyzed by principal component analysis (PCA). The PCA results clearly indicated that the infection of C. albicans can be divided into three phases that include adhesion, invasion and damage phases. The results were highly consistent with subsequent histological analysis. Furthermore, we found the primary ontology function of genes with significant variations in both C. albicans and zebrafish is iron related. Most of the iron related genes in C. albicans were over-expressed in late stage, while most of the iron related genes in zebrafish were suppressed at the same phase of infection. It suggested that the iron homeostasis function of the host was shut-down when massive hemorrhage in zebrafish occurred during later stages of infection. At the same time, the iron scavenging function of C. albicans was activated. This implied the competition for iron is an important issue between the host and the fungal pathogen during infection. When we administered excess iron into the microenvironment of infection site, the infection process was significantly delayed. That indicated the virulence of C. albicans is correlated with its protein-bond iron scavenging strategies. Our finings not only provided dynamic mechanistic views of the iron competition but also highlighted the potential regulatory schemes in fungal pathogenesis.
2013-08-26 | GSE32117 | GEO
Project description:Phenotypic plasticity, the ability to switch between different morphological types, plays critical roles in environmental adaptation, leading to infections, and allowing for sexual reproduction in pathogenic Candida species. Candida tropicalis, which is both an emerging human fungal pathogen and an environmental fungus, can switch between two heritable cell types termed white and opaque. In this study, we report the discovery of a novel phenotype in C. tropicalis, named the gray phenotype. Similar to Candida albicans and Candida dubliniensis, white, gray, and opaque cell types of C. tropicalis also form a tristable switching system, where gray cells are relatively small and elongated. In C. tropicalis, gray cells exhibit intermediate levels of mating competency and virulence in a mouse systemic infection model compared to the white and opaque cell types, express a set of cell type-enriched genes, and exhibit both common and species-specific biological features. The key regulators of white-opaque transitions, Wor1 and Efg1, are not required for the gray phenotype. A comparative study of the gray phenotypes in C. tropicalis, C. albicans, and C. dubliniensis provides clues to explain the species differences in terms of virulence, ecological niches, and prevalence among these three species.
2017-01-30 | GSE81514 | GEO