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PROVIDER: PRJNA1065146 | ENA |
REPOSITORIES: ENA
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Project description:Invasive fungal infections (IFIs) are difficult to treat. Few effective antifungal drugs are available and many have problems with toxicity, efficacy and drug-resistance. To overcome these challenges, existing therapies may be enhanced using more than one agent acting in synergy. Previously, we have found amphotericin B (AMB) and the iron chelator, lactoferrin (LF), were synergistic against Cryptococcus neoformans and Saccharomyces cerevisiae. This study investigates the mechanism of AMB+LF synergy using RNA-seq in Cryptococcus neoformans H99.
2019-09-08 | GSE130375 | GEO
Project description:A family of APSES transcription factor is known to be fungal-specific transcriptional regulators and play important roles in governing growth, differentiation, and virulence of diverse fungal pathogens. Yet none of APSES-like transcription factors have been identified and investigated in a basidiomycetous fungal pathogen, Cryptococcus neoformans. In the present study we discovered an APSES-like transcription factor, Msa1 (Mbp1/Swi4-like APSES protein 1), as one of novel flucytosine-responsive genes (total 194 genes) identified through comparative transcriptome analysis of C. neoformans hybrid sensor kinase mutants, tco1 and tco2 mutants, which displayed differential flucytosine-susceptibility. Supporting the microarray data, Northern blot and quantitative RT-PCR analysis confirmed that expression of MSA1 is rapidly induced in response to flucytosine in the wild-type strain, but not in the tco1 and tco2 mutants. Furthermore, C. neoformans with deletion of the MSA1 gene exhibited increased susceptibility to flucytosine. Intriguingly, Msa1 plays pleiotropic roles in diverse cellular process of C. neoformans. Msa1 positively regulates ergosterol biosynthesis and thereby its inhibition confers increased susceptibility and resistance to amphotericin B and azole drugs, respectively. Msa1 is also involved in DNA damage repair counteracting genotoxic stresses. During sexual differentiation Msa1 represses pheromone production, but promotes cell-cell fusion. Furthermore Msa1 is required for production of antioxidant melanin pigment and full virulence of C. neoformans. Finally we also performed DNA microarrray analysis to identify Msa1-regulated genes in C. neoformans. A majority of them were found to be involved in cell cycle regulation and DNA repair. Therefore, this study provides a novel antifungal therapeutic method for treatment of cryptococcosis. There are more than 95% of genome homology between JEC21 and H99. Therefore 24 slides of JEC21 (cryptococcus neoformans var. neoformans serotype D) 70-mer oligo are used in this analysis, 3 biological replicate experiments are performed, total RNAs are extracted under 2 conditions (with or without treatment of Flucytosine) with 4 strains from H99 (H99 Wild type strain (Cryptococcus neoformans var. grubii serotype A), tco1Δ , tco2Δ , skn7Δ), We use the mixed all of total RNAs from this experiment as a control RNA. We use Cy5 as Sample dye and Cy3 as a control dye.
2011-06-23 | E-GEOD-30154 | biostudies-arrayexpress
Project description:A family of APSES transcription factor is known to be fungal-specific transcriptional regulators and play important roles in governing growth, differentiation, and virulence of diverse fungal pathogens. Yet none of APSES-like transcription factors have been identified and investigated in a basidiomycetous fungal pathogen, Cryptococcus neoformans. In the present study we discovered an APSES-like transcription factor, mbs1 (Mbp1/Swi4-like APSES protein 1), as one of novel flucytosine-responsive genes (total 194 genes) identified through comparative transcriptome analysis of C. neoformans hybrid sensor kinase mutants, tco1 and tco2 mutants, which displayed differential flucytosine-susceptibility. Supporting the microarray data, Northern blot and quantitative RT-PCR analysis confirmed that expression of mbs1 is rapidly induced in response to flucytosine in the wild-type strain, but not in the tco1 and tco2 mutants. Furthermore, C. neoformans with deletion of the mbs1 gene exhibited increased susceptibility to flucytosine. Intriguingly, mbs1 plays pleiotropic roles in diverse cellular process of C. neoformans. mbs1 positively regulates ergosterol biosynthesis and thereby its inhibition confers increased susceptibility and resistance to amphotericin B and azole drugs, respectively. mbs1 is also involved in DNA damage repair counteracting genotoxic stresses. During sexual differentiation mbs1 represses pheromone production, but promotes cell-cell fusion. Furthermore mbs1 is required for production of antioxidant melanin pigment and full virulence of C. neoformans. Finally we also performed DNA microarrray analysis to identify mbs1-regulated genes in C. neoformans. A majority of them were found to be involved in cell cycle regulation and DNA repair. Therefore, this study provides a novel antifungal therapeutic method for treatment of cryptococcosis. total RNAs are extracted 2 strains from H99 (H99 Wild type strain (Cryptococcus neoformans var. grubii serotype A), mbs1Δ), We use the mixed all of total RNAs from this experiment as a control RNA. We use Cy5 as Sample dye and Cy3 as a control dye.
2011-06-23 | E-GEOD-30156 | biostudies-arrayexpress
Project description:Cryptococcus neoformans is a human fungal pathogen responsible for fatal infections, especially in patients with a depressed immune system. Overexposure to antifungal drugs due to prolonged treatment regimens and structure-similar applications in agriculture have weakened the efficacy of current antifungals in the clinic. The rapid evolution of antifungal resistance urges the discovery of new compounds that inhibit fungal virulence factors, rather than directly killing the pathogen as alternative strategies to overcome disease and reduce selective pressure towards resistance. Recent studies, including our own, have highlighted the antimicrobial properties of natural sources, such as invertebrates, against human fungal pathogens, including C. neoformans, through virulence factor impairment. Here, we evaluated the efficacy of freshwater mussel extracts (crude and clarified) against virulence factor production (i.e., thermotolerance, melanin, capsule, and biofilm) in C. neoformans. Similarly, we demonstrated the critical potential of these extracts to increase the susceptibility of the pathogen to fluconazole across resistant strains, overcoming a globally devastating problem. Additionally, we measured the inhibitory activity of the extracts against peptidases related to fungal virulence and drug resistance. Furthermore, we integrated these phenotypic findings with quantitative proteomics profiling to define distinct signatures of each treatment and validated a new mechanism of anti-virulence action for a selected extract. By understanding the mechanisms driving the antifungal activity of mussels, we may develop innovative treatments for fungal infections lacking susceptibility to conventional drugs.
2024-01-27 | PXD043643 | Pride
Project description:Lysine acetylation and ubiquitination are one of many protein modifications and play a crucial role in the biological regulation of many organisms, but little is known about the relationship between acetylation and ubiquitination few. Here, the Isw1 protein is an important member of the chromatin remodeling complex, and we performed single-protein modification mass spectrometry detection of the C. neoformans Isw1 protein and site mutations for both detected modifications. The data showed that the two modifications of Cryptococcus neoformans Isw1 protein have a balance of each other. Acetylation can maintain protein stability and maintain protein function, while ubiquitination can reduce protein level and maintain Isw1 protein expression. The expression level of Isw1 protein leads to resistance to antifungal drugs. These results reveal the resistance mechanism of Isw1 protein of Cryptococcus neoformans to antifungal drugs.
2022-12-26 | PXD037150 | Pride
Project description:The opportunistic pathogen Cryptococcus neoformans causes fungal meningoencephalitis in immunocompromised individuals. In previous studies, we found that the Hap complex in this pathogen represses genes encoding mitochondrial respiratory functions and TCA cycle components under low-iron conditions. The orthologous Hap2/3/4/5 complex in Saccharomyces cerevisiae exerts a regulatory influence on mitochondrial functions and Hap4 is subject to glucose repression via the carbon catabolite repressor Mig1. In this study, we explored the regulatory link between a candidate ortholog of the Mig1 protein and the HapX component of the Hap complex in C. neoformans. This analysis revealed repression of MIG1 by HapX and activation of HAPX by Mig1 in low iron conditions, and Mig1 regulation of mitochondrial functions including respiration, tolerance for reactive oxygen species, and expression of genes for iron-consuming and iron-acquisition functions. Consistent with these regulatory functions, a mig1Î mutant had impaired growth on inhibitors of mitochondrial respiration and ROS inducers. Furthermore, deletion of MIG1 provoked a dysregulation in nutrient sensing via the TOR pathway and impacted the pathway for cell wall remodeling. Importantly, loss of Mig1 increased susceptibility to fluconazole thus further establishing a link between azole antifungal drugs and mitochondrial function. Mig1 and HapX were also required together for survival in macrophages, but Mig1 alone had a minimal impact on virulence in mice. Overall, these studies provide novel insights into a HapX/Mig1 regulatory network and reinforce an association between mitochondrial dysfunction and drug susceptibility that may provide new targets for the development of antifungal drugs. In this study, transcription profiles of WT and mig1D mutant strains of Cryptococcus neoformans were compared in a dye-swap experiment following 6hr exposure to Low Iron Medium (LIM) or LIM + 100mM FeCl3.
2015-12-17 | E-GEOD-76063 | biostudies-arrayexpress
Project description:WD40 motif-containing Msi1-like (MSIL) proteins play pleiotropic cellular functions as a negative regulator of the Ras/cAMP-pathways and a component of chromatin assembly factor-I (CAF-I), and yet have not been studied in fungal pathogens. Here we identified and characterized an MSIL protein, Msl1, in Cryptococcus neoformans, which can cause fatal meningoencephalitis in humans. Notably, Msl1 was not a functional ortholog for the yeast Msi1 but played pleiotropic roles in C. neoformans in both cAMP-dependent and -independent manners but mainly Ras-independently. Msl1 negatively controlled antioxidant melanin production and sexual differentiation, which can be repressed by inhibiting the cAMP-signaling pathways. In contrast, Msl1 controlled thermotolerance, diverse stress responses, and antifungal drugs resistance in Ras/cAMP-independent manners. Cac2, which is the second CAF-I component, appeared to play both redundant and distinct function with Msl1. Msl1 is required for full virulence of C. neoformans. Transcriptome and proteomic analysis identified a group of Msl1-regulated genes or -interacting proteins, respectively, which mostly include stress-related genes, including HSP12, HSP78, SSA1, SSA4, and STM1. Furthermore, we identified the third putative component of CAF-1, Rlf2, in C. neoformans. In conclusion, this study demonstrated the pleiotropic roles of Msl1 in human fungal pathogen C. neoformans, providing a novel antifungal therapeutic target. There is more than 95% genome homology between JEC21 and H99. Therefore, 6 slides of JEC21 (Cryptococcus neoformans var. neoformans serotype D) 70-mer oligos are used in this analysis. Total RNAs are extracted from 2 strains from H99 (H99 wild-type strain (Cryptococcus neoformans var. grubii serotype A), msl1M-NM-^T). 3 biological replicate experiments are performed for each strain. We use the mix of all total RNAs from this experiment as the control RNA. We use Cy3 as the test sample dye and Cy5 as the control dye.
2012-08-23 | E-GEOD-40303 | biostudies-arrayexpress
Project description:Purpose: The purpose of this study is to define the mechanism of antifungal action of the vanillin derivative, o-vanillin, against Cryptococcus neoformans Methods: mRNA profiles of C. neoformasn cells cultured with or without o-vanillin were generated by RNA-Seq, using Illumina GAIIx. The sequence reads that passed quality filters were mapped to reference genome and the normalized RPKM values were calculated by CLC Genomics Workbench. Results: o-vanillin significantly altered global transcript profiles, induces oxidative stress, and interferes mitochondrial functions in C. neoformans. Conclusions: o-vanillin can be considered as the effective antifungal drug candidate.
2014-10-22 | GSE52645 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE29627: Chromosome copy number variation in Cryptococcus neoformans influences virulence and occurs in isolates from AIDS patients: CBS7779 black and white strains GSE29671: Chromosome copy number variation in Cryptococcus neoformans influences virulence and occurs in isolates from AIDS patients: clinal and environmental strains Refer to individual Series
2011-05-31 | E-GEOD-29675 | biostudies-arrayexpress