Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans
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ABSTRACT:
PROVIDER: PRJNA1026965 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26359136_1.fastq.gz | Fastqsanger.gz | |||
| SRR26359136_2.fastq.gz | Fastqsanger.gz | |||
| SRR26359137_1.fastq.gz | Fastqsanger.gz | |||
| SRR26359137_2.fastq.gz | Fastqsanger.gz | |||
| SRR26359138_1.fastq.gz | Fastqsanger.gz |
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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:Due to the scarcity of transition metals within the human host, fungal pathogens have evolved sophisticated mechanisms to uptake and utilize these micronutrients at the infection interface. While considerable attention was turned to iron and copper acquisition mechanisms and their importance in fungal fitness, less was done regarding either the role of manganese (Mn) in infectious processes or the cellular mechanism by which fungal cells achieve their Mn-homeostasis. Here, we undertook transcriptional profiling in the pathogenic fungus Candida albicans experiencing both Mn starvation and excess to capture biological processes that are modulated by this metal. We uncovered that Mn scarcity influences diverse processes associated with fungal fitness including invasion of host cells and antifungal sensitivity. We show that Mn levels influence the abundance of iron and zinc emphasizing the complex crosstalk between metals. The deletion of SMF12, a member of Mn Nramp transporters, confirmed its contribution to Mn uptake. smf12 was unable to form hyphae and damage host cells and exhibited sensitivity to azoles. We found that the unfolded protein response (UPR), likely activated by decreased glycosylation under Mn limitation, was required to recover growth when cells were shifted from an Mn-starved to an Mn-repleted medium. RNA-seq profiling of cells exposed to Mn excess revealed that UPR was also activated. Furthermore, the UPR signaling axis Ire1-Hac1 was required to bypass Mn toxicity. Collectively, this study underscores the importance of Mn homeostasis in fungal virulence and comprehensively provides a portrait of biological functions that are modulated by Mn in a fungal pathogen.ImportanceTransition metals such as manganese provide considerable functionality across biological systems as they are used as cofactors for many catalytic enzymes. The availability of manganese is very limited inside the human body. Consequently, pathogenic microbes have evolved sophisticated mechanisms to uptake this micronutrient inside the human host to sustain their growth and cause infections. Here, we undertook a comprehensive approach to understand how manganese availability impacts the biology of the prevalent fungal pathogen, Candida albicans. We uncovered that manganese homeostasis in this pathogen modulates different biological processes that are essential for host infection which underscores the value of targeting fungal manganese homeostasis for potential antifungal therapeutics development.
| S-EPMC10964418 | biostudies-literature
Project description:In our previous work, we generated a mutant of the Mn NRAMP transporter, smf12, to investigate the impact of Mn scarcity on the biology of C. albicans. We found that inactivation of SMF12 resulted in attenuated virulence, increased sensitivity to azoles, and activation of the unfolded protein response (UPR). To investigate further cellular processes affected in smf12, we carried out RNA-seq profiling under manganese (Mn) starvation. The transcriptional profile of smf12 growing in the Mn-free SC medium (SC-Mn) was compared to that of the WT strain growing under similar conditions. Upregulated transcripts in smf12 were mainly enriched in processes related to the synthesis and the processing of the three core polysaccharides of the fungal cell wall namely chitin (CHS2, 7, CDA2, CHT4), glucan (KRE1, 9, UTR2, PNG2) and phosphomannan (MNN1, 15, 41, 42, 43, 45, 47, BMT3, 4, 6, 7, KTR4, DFG5, FAV3). Transcripts related to cell wall signaling proteins and transcriptional control including the Cek1 MAP kinase, the histidine kinase Chk1 and the transcription factor Crz1 were also upregulated. This transcriptional signature is reminiscent of a situation in which the cell wall is undergoing remodeling in response to a specific perturbation.
2024-12-31 | GSE283948 | GEO
Project description:Manganese homeostasis modulates glucan and chitin unmasking in Candida albicans
| PRJNA1196367 | ENA
Project description:The ability of the opportunistic yeast Candida albicans to acquire and maintain homeostatic levels of manganese (Mn), particularly in the metal-limited host environment, is an important determinant of its fitness. Although significant focus has been given to mechanisms of iron and copper acquisition and their roles in C. albicans fitness, little is known about how this yeast maintain and control Mn homeostasis. Here, we presented a comparative proteomic and phospho-proteomic analysis in C. albicans cells experiencing Mn starvation. Both proteome and phosphoproteome of the C. albicans reference strain SC5314 growing in Mn-depleted medium were compared to those of cells thriving in Mn-repleted medium. Samples were collected in four biological replicates at two time-points (5 and 90 min). LC–MS/MS identified approximately 1500 differentially abundant proteins and over 140 phosphorylated proteins.
2025-06-12 | PXD064206 | Pride
Project description:Co-infections of Candida albicans and Staphylococcus aureus can significantly increase morbidity and mortality. This synergism is linked to the interactions between C. albicans and S. aureus that allow for staphylococcal co-invasion and dissemination. While it is known that virulence factors contribute to this process, the effect of C. albicans-S. aureus coculturing on virulence factors composition and macrophage-mediated inflammation remain unknown. In this study, we used mass spectrometry-proteomics to investigate the effect of coculturing on the composition of the >3 kDa protein fraction of the S. aureus and C. albicans secretome, as well as the secretomal cytotoxicity and proinflammatory effects on human oral cells and immune cells. Results showed that coculturing of C. albicans and S. aureus promoted the secretion of 7 cytolytic, 11 proteolytic, and 3 lipolytic extracellular virulence factors (ECVFs). While the majority of differentially released C. albicans ECVFs were attributable to Als1/Als3-mediated interactions, changes in S. aureus secretomal ECVF composition were mainly attributable to the presence of C. albicans or its pH maintenance. By analysing both secreted and non-secreted virulence factors, it appears that coculturing promotes C. albicans hypha formation together with β-glucan masking, suggesting that coculturing enhances both C. albicans invasion and immune evasion. In addition, coculturing increased the cytotoxic potential of the secretome towards human oral epithelial cells and macrophages compared to the summed cytotoxic effect of both monoculture secretomes. Under non-cytotoxic conditions, the secretome of C. albicans-S. aureus coculture promoted macrophage activation and increased gene transcription of pro-inflammatory pathways compared to monoculture secretomes. Surprisingly, ALS1/ALS3 knock out has marginal effects on the secretome-increased proinflammation in macrophages. Our findings support that C. albicans and S. aureus reciprocally promotes their virulence potential, cytotoxicity, and proinflammatory effects, which may provide insights into the synergistic lethality during their coinfection in vivo.
2025-09-10 | GSE289787 | GEO
Project description:Abstract: Candida parapsilosis and Candida albicans are human fungal pathogens that belong to the CUG clade in the Saccharomycotina. In contrast to C. albicans, relatively little is known about the virulence properties of C. parapsilosis, a pathogen particularly associated with infections of premature neonates. We describe here the construction of >200 C. parapsilosis strains carrying double allele deletions of transcription factors, protein kinases and species-specific genes. Two independent deletions were constructed for each target gene. Growth in > 40 conditions was tested, including carbon source, temperature, and the presence of antifungal drugs. The phenotypes were compared to C. albicans strains with deletions of orthologous transcription factors. We found that many phenotypes are shared between the two species, such as the role of Upc2 as a regulator of azole resistance. Others are unique. For example, Cph2 plays a role in the hypoxic response in C. parapsilosis and not in C. albicans. We found extensive divergence between the biofilm regulators of the two species. We identified 7 transcription factors and one protein kinase that are required for biofilm development in C. parapsilosis. Only three (Efg1, Bcr1, and Ace2) have similar effects on C. albicans biofilms, whereas Cph2, Czf1, Gzf3 and Ume6 have major roles in C. parapsilosis only. In addition, two transcription factors (Brg1 and Tec1) with well-characterized roles in biofilm formation in C. albicans do not have the same function in C. parapsilosis. We also compared the transcription profile of C. parapsilosis and C. albicans biofilms. Our analysis suggests the processes shared between the two species are predominantly metabolic.
2014-07-21 | GSE57451 | 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
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: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