Targeting epigenetic regulators to overcome drug resistance in the emerging human fungal pathogen Candida auris
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ABSTRACT:
PROVIDER: PRJNA1245342 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32950488_1.fastq.gz | Fastqsanger.gz | |||
| SRR32950488_2.fastq.gz | Fastqsanger.gz | |||
| SRR32950489_1.fastq.gz | Fastqsanger.gz | |||
| SRR32950489_2.fastq.gz | Fastqsanger.gz | |||
| SRR32950490_1.fastq.gz | Fastqsanger.gz |
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Project description:The rise of drug-resistant fungal species, such as Candida auris, poses a serious threat to global health, with mortality rates exceeding 40% and resistance rates surpassing 90%. The limited arsenal of effective antifungal agents underscores the urgent need for novel strategies. Here, we systematically evaluate the role of histone H3 post-translational modifications in C. auris drug resistance, focusing on acetylation mediated by Gcn5 and Rtt109, and methylation mediated by Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibit varying degrees of antifungal drug sensitivity. Notably, we discover that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulates key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through the calcineurin signaling pathway and transcription factor Cas5. In infection models using Galleria mellonella and immunocompromised mice, GCN5 deletion significantly reduces the virulence of C. auris. Furthermore, the Gcn5 inhibitor CPTH2synergizes with caspofungin in vitro and in vivo without notable toxicity. These findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris, positioning it as a promising therapeutic target for combating invasive fungal infections.
2025-04-05 | GSE293594 | GEO
Project description:Candida auris is amongst the most important emerging fungal pathogens, yet mechanistic insights in its immune recognition and control are lacking. Here, we integrate transcriptional and functional immune cell profiling to uncover innate anti-C. auris defense mechanisms. C. auris induces a specific transcriptome in human mononuclear cells, a stronger cytokine response compared to C. albicans, but a lower macrophage lysis capacity. C. auris-induced innate immune activation is mediated through recognition of C-type lectin receptors, mainly elicited by structurally unique C. auris mannoproteins. In in-vivo experimental models of disseminated candidiasis, C. auris was less virulent than C. albicans. Collectively, these results demonstrate that C. auris is a strong inducer of innate host defense and identify possible targets for adjuvant immunotherapy.
2020-07-23 | GSE154911 | GEO
Project description:The ‘superbug’ Candida auris has been ranked as a priority fungal pathogen and is becoming a serious threat to public health. However, the underlying mechanisms of real-world pathogen-host interactions remain elusive, in part due to the lack of powerful immunocompetent animal models. In this study, we report that selected wild-type strains of Drosophila melanogaster can be developed as a promising infection model to recapitulate C. auris bloodstream infection. The systemic and organ-specific responses to C. auris infection in vivo were evaluated, as well as the corresponding transcriptional profiling. Our findings confirm that Toll and JAK-STAT signaling pathways mediate antifungal responses in the Drosophila model following C. auris infection. Moreover, we identified certain conserved novel factors required for host-C. auris interactions, highlighting the fly model's potential to reveal subtle immune mechanisms not readily observed in mammalian systems. Taken together, our work demonstrates that wild-type Drosophila offers a robust immunocompetent animal model for the further in-depth investigation of dynamic C. auris-host interactions in vivo.
2025-10-12 | GSE279369 | GEO
Project description:Filamentous cell growth is a vital property of fungal pathogens. The mechanisms of filamentation in the emerging multidrug-resistant fungal pathogen Candida auris are poorly understood. Here, we show that exposure of C. auris to glycerol triggers a rod-like filamentation-competent (RL-FC) phenotype, which forms elongated filamentous cells after a prolonged culture period. Whole-genome sequencing analysis reveals that all RL-FC isolates harbor a mutation in the C2H2 zinc finger transcription factor-encoding gene GFC1 (Gfc1 variants). Deletion of GFC1 leads to an RL-FC phenotype similar to that observed in Gfc1 variants. We further demonstrate that GFC1 mutation causes enhanced fatty acid β-oxidation metabolism and thereby promotes RL-FC/filamentous growth. This regulation is achieved through a Multiple Carbon source Utilizer (Mcu1)-dependent mechanism. Interestingly, both the evolved RL-FC isolates and the gfc1Δ mutant exhibit an enhanced ability to colonize the skin. Our results reveal that glycerol-mediated GFC1 mutations are beneficial during C. auris skin colonization and infection.
2024-06-12 | PXD047167 | Pride
Project description:<p>Filamentous cell growth is a vital property of fungal pathogens. The mechanisms of filamentation in the emerging multidrug-resistant fungal pathogen Candida auris are poorly understood. Here, we show that exposure of C. auris to glycerol triggers a rod-like filamentation-competent (RL-FC) phenotype, which forms elongated filamentous cells after a prolonged culture period. Whole-genome sequencing analysis reveals that all RL-FC isolates harbor a mutation in the C2H2 zinc finger transcription factor-encoding gene <em>GFC1</em> (Gfc1 variants). Deletion of GFC1 leads to an RL-FC phenotype similar to that observed in Gfc1 variants. We further demonstrate that GFC1 mutation causes enhanced fatty acid β-oxidation metabolism and thereby promotes RL-FC/filamentous growth. This regulation is achieved through a Multiple Carbon source Utilizer (Mcu1)-dependent mechanism. Interestingly, both the evolved RL-FC isolates and the gfc1Δ mutant exhibit an enhanced ability to colonize the skin. Our results reveal that glycerol-mediated GFC1 mutations are beneficial during C. auris skin colonization and infection.</p>
2024-07-04 | MTBLS9053 | MetaboLights
Project description:Host immune response against the emerging fungal pathogen Candida auris: transcriptional and functional insights
| PRJNA647871 | ENA
Project description:Combination therapies can be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the interaction between aprepitant, an antiemetic agent, and azole drugs against different Candida species including the emerging multidrug-resistant C. auris. Particularly, aprepitant enhanced the antifungal activity of itraconazole against C. auris by reducing its minimum inhibitory concentration (MIC) by 2-8 folds. Using Caenorhabditis elegans as an in vivo infection model, the aprepitant/itraconazole combination significantly prolonged the survival of the infected nematodes by ~90% and reduced the fungal burden by ~92% relative to the untreated control. Interestingly, the aprepitant/itraconazole combination exerted a potent fungicidal activity against both planktonic and adherent C. auris biofilms. Further, aprepitant/itraconazole displayed broad-spectrum synergistic interactions against other medically important Candida species including C. albicans, C. krusie, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 031). Comparative transcriptomic profiling indicated aprepitant/itraconazole interferes significantly with metal ions homeostasis and compromises the ROS (reactive oxygen species) detoxification ability of C. auris. This study presents aprepitant as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation.
2020-10-19 | GSE148749 | GEO
Project description:Candida auris is an emerging infectious agent and WHO critical priority fungal pathogen. Rising pan-resistance, massive nosocomial outbreaks and diagnostic challenges complicate clinical treatment, with an associated human mortality rate of 45%. Importantly, in vivo gene expression of C. auris during infection has not been described to date. We developed the novel thermotolerant teleost fish embryo yolk-sac microinjection model of Aphanius dispar (Arabian Killifish, AK) for infection by each of the five major C. auris clades. This model enabled dual host-pathogen RNA-seq at 24 and 48 hours post injection (HPI) at mammalian temperature (37 °C), which has not been reported in other teleost fish models. Host gene expression indicated features of nutritional and innate immune responses, including haem-oxygenase and C-type lectin receptor expression. We identified an in vivo transcriptome signature common to all five clades of C. auris compared to in vitro expression that was highly enriched for putative xenosiderophore transmembrane transporters. We describe the seventeen-member xenosiderophore transport candidate family in terms of diverse in-host patterns of expression and cross-kingdom functional prediction. We discovered that only the basal clade V isolate formed filaments in vivo, corresponding with Candida-typical and atypical hypha-formation genetic signals, such as the novel adhesin SCF1. Furthermore, clades that were more virulent (I or IV vs II or III) were strongly characterised by upregulation of the majority of genes at the mating-type locus (MTL), including non-mating genes, consistent with a role for the MTL in C. auris pathogenicity. We hypothesise that both xenosiderophore transport genes and the MTL may play critical roles in C. auris virulence, and are urgent targets for potential therapy.
2025-11-13 | GSE277854 | GEO
Project description:The limited number of antifungals and the emergence of multidrug-resistant Candida auris pose a significant challenge to human medicine. Here, we utilized combinatorial drug therapy as an approach to augment the activity of current azole antifungals against C. auris. We evaluated the fluconazole chemosensitization activity of 1547 FDA-approved drugs and clinical molecules against an azole-resistant strain of C. auris. This led to the discovery that lopinavir, an antiviral drug, is a potent agent capable of sensitizing C. auris to the effect of azole antifungals. At a therapeutically achievable concentration (4-8 µg/ml), lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole, against C. auris (ΣFICI ranged from 0.05-0.50). The lopinavir/itraconazole combination enhanced the survival rate of C. auris-infected Caenorhabditis elegans by 90% and reduced the fungal burden in infected nematodes by 88.5% (p < 0.05). Moreover, lopinavir enhanced the antifungal activity of itraconazole against other medically important Candida species including C. albicans, C. tropicalis, C. glabrata, C. tropicalis, and C. parapsilosis. Comparative transcriptomic profiling revealed that lopinavir interferes with glucose permeation and ATP synthesis. This compromises the function of the efflux pumps presents in C. auris enhancing sensitivity to azole antifungals, as demonstrated by Nile red efflux assays. This study presents lopinavir as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation against recalcitrant Candida infections.
2020-10-06 | GSE148341 | GEO
Project description: Not available
| S-EPMC7652928 | biostudies-literature