Evaluating the mode of Antifungal action of Heat-Stable Antifungal Factor (HSAF) in Neurospora crassa
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ABSTRACT:
ORGANISM(S): Neurospora crassa
PROVIDER: GSE195441 | GEO | 2022/01/28
REPOSITORIES: GEO
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Project description:The emergence of drug-resistant fungal strains is a threat to human health. Identifying targets that increase the susceptibility of fungal pathogens to current therapies will significantly improve outcomes. Tra1 is an essential component of the SAGA and NuA4 transcriptional co-activator complexes and is linked to multiple cellular processes associated with the yeast response to antifungal drugs. This submission contains RNA sequencing data from Candida albicans strain expressing a Tra1 mutant with three arginine to glutamine mutations in the PI3K domain (tra1Q3; Berg et al., 2018) treated with or without the antifungal caspofungin. Our goal was to identify genes regulated by Tra1 in C. albicans and identify genes with differential responses in the mutant tra1 strain upon capsofungin relative to the wild-type strain. We identified 68 genes that were differentially expressed when the tra1Q3 strain was treated with caspofungin, as compared to gene expression changes induced by either tra1Q3 or caspofungin alone. Included in this set were genes involved in cell wall maintenance, adhesion and filamentous growth. As a critical component of both SAGA and NuA4, Tra1 is uniquely positioned to regulate the yeast antifungal response and emerges, through targeting its PI3K domain, as a promising new therapeutic target for fungal infections.
2021-03-17 | GSE168988 | GEO
Project description:The systemic infections by peptogenous fungi member of the genera Candida and Aspergillus represent a serious threat for public health. During previous research we have successfully identified a family of compounds active against different Candida spp. including strains resistant to antifungal drugs currently on the market. We have further refined our knowledge on this field by identifying a possible molecular target that could justify the activity of these compounds. The research of the mode of action of the compounds object of this manuscript was supported also by fluorescent microscopy of labeled derivatives. Transcriptional data indicates that one of the macrocyclic antifungal induces a drug response involving ATP binding cassette transporters. Moreover the data show that the macrocyclic antifungal decrease expression of cell wall biosynthesis genes. Moreover, the quality of the compounds and their potential was tested in vivo revealing a promising profile in particular against fungal infection caused by resistant strains
2015-04-01 | GSE65396 | GEO
Project description:Human serum amyloid A (SAA) is a major acute phase protein and shows a massive increase of concentration in plasma during inflammation. In the current study, we report that recombinant human and mouse SAA1 (rhSAA1 and rmSAA1) have a potent antifungal activity against the major fungal pathogen Candida albicans. rhSAA1 binds to the cell surface of C. albicans and promotes cell aggregation. At high concentrations, rhSAA1 disrupts the membrane integrity and induces rapid cell death of C. albicans. Further investigation demonstrates that rhSAA1 targets on the cell wall adhesin Als3 of C. albicans. Inactivation of ALS3 in C. albicans leads to remarkably decreased cell aggregation and death upon rhSAA1 treatment, implying that Als3 plays a critical role in SAA1 sensing. Moreover, deletion of the ALS3 transcriptional regulators such as AHR1, BCR1, and EFG1 in C. albicans results in a similar effect on cell responses to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling analysis indicates that rhSAA1 has a remarkable impact on the expression of cell wall- and metabolism-related genes in C. albicans. Our finding of the antifungal activity of rhSAA1 against C. albicans expands the function of this protein and would provide new insights into the understanding of the host-Candida interaction during infections.
2019-09-01 | GSE128598 | GEO
Project description:The systemic infections by peptogenous fungi member of the genera Candida and Aspergillus represent a serious threat for public health. During previous research we have successfully identified a family of compounds active against different Candida spp. including strains resistant to antifungal drugs currently on the market. We have further refined our knowledge on this field by identifying a possible molecular target that could justify the activity of these compounds. The research of the mode of action of the compounds object of this manuscript was supported also by fluorescent microscopy of labeled derivatives. Transcriptional data indicates that one of the macrocyclic antifungal induces a drug response involving ATP binding cassette transporters. Moreover the data show that the macrocyclic antifungal decrease expression of cell wall biosynthesis genes. Moreover, the quality of the compounds and their potential was tested in vivo revealing a promising profile in particular against fungal infection caused by resistant strains Gene expression was measured in Candida albians CAF2-1 exposed to the macrocyclic compound FR59 at 3 µM at two time points (15 min and 45 min), The one-color system was used. Three independent experiments were performed using non-exposed cells, 15 min and 45 min exposed cells.
2015-04-01 | E-GEOD-65396 | biostudies-arrayexpress
Project description:Purpose: Evaluate the transcriptional profile of Neurospora crassa cells treated with a group of novel antifungal compounds Methods: Conidial suspensions were obtained and 1 x 106 cells/ml incubated in minimal medium for 6 hours (26ºC, 140 rpm, constant light) followed by the addition of the indicated compound (or DMSO) and growth for 1 more hour. Cells were harvested using 0.45 μm filters and immediately frozen in liquid nitrogen. Total RNA was isolated by the Trizol-Phenol-Chloroform method. After digestion of 25 μg RNA with TURBO DNAse (Life Technologies), mRNA was purified using Dynabeads oligo(dT) magnetic beads (Life Technologies). The mRNA was chemically fragmented using the Ambion RNA fragmentation kit (Life Technologies). First and second strand cDNA synthesis was achieved using appropriate kits (Life Technologies). The illumina TruSeq kit was employed to generate the cDNA libraries with indexing adapters essentially following the manufacturerâs protocol. After purification of the libraries with AMPure XP beads (Roche), the quality of the libraries was analysed in a Agilent 2100 Bioanalyzer. The cDNA libraries were sequenced in a illumina HiSeq2000 and single reads of 50 bp were obtained. Sequencing data was handled essentially with Tophat, Cufflinks and Cuffdiff. Expression levels are presented as Fragments Per Kilobase of transcript per Million mapped reads (FPKM). Results: XP13 promoted a particularly active transcriptional response. Functional enrichment analysis of the genes with altered expression revealed novel pathways that are affected by these compounds. Conclusions: These compounds are active in Neurospora crassa and we anticipate that this and future studies will ascertain their potential as antifungal agents. The transcriptional profile of Neurospora crassa wild type cells exposed with a group of novel compounds with antifungal activity was analysed using illumina HiSeq2000 and single reads of 50 bp.
2015-11-25 | E-GEOD-53040 | biostudies-arrayexpress
Project description:Bdellovibrio bacteriovorus is a Gram-negative bacterium that is a pathogen of other Gram-negative bacteria, including many bacteria which are pathogens of humans, animals and plants. As such Bdellovibrio has potential as a biocontrol agent, or living antibiotic. B. bacteriovorus HD100 has a large genome and it is not yet known which of it encodes the molecular machinery and genetic control of predatory processes. We have tried to fill this knowledge-gap using mixtures of predator and prey mRNAs to monitor changes in Bdellovibrio gene expression at a timepoint of early-stage prey infection and prey killing in comparison to control cultures of predator and prey alone and also in comparison to Bdellovibrio growing axenically (in a prey-or host independent “HI” manner) on artificial media containing peptone and tryptone. From this we have highlighted genes of the early predatosome with predicted roles in prey killing and digestion and have gained insights into possible regulatory mechanisms as Bdellovibrio enter and establish within the prey bdelloplast. Approximately seven percent of all Bdellovibrio genes were significantly up-regulated at 30 minutes of infection- but not in HI growth- implicating the role of these genes in prey digestion. Five percent were down-regulated significantly, implicating their role in free-swimming, attack-phase physiology. This study gives the first post- genomic insight into the predatory process and reveals some of the important genes that Bdellovibrio expresses inside the prey bacterium during the initial attack. Keywords: Transcriptional analysis
2009-12-09 | GSE9269 | GEO
Project description:Fungal infections have become a clinical challenge due to the emergence of drug-resistance of invasive fungi and a rapid increase of novel pathogens. The development of drug resistance has further restricted the use of antifungal agents. Therefore, there is anurgentneedto searchforalternativetreatmentoptions for Cryptococcus neoformans (C. neoformans). Disulfiram (DSF) has a high human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. In contrast, the effect of DSF on Cryptococcus has yet to be thoroughly researched. This study investigated the antifungal effect and mechanism of DSF againstC. neoformansto provide a new theoretical foundation for treating Cryptococcal infections. In vitro studies demonstrated that DSF inhibitedCryptococcusat minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects were also observed with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. In vivo, DSF exerted asignificantprotectiveeffectforGalleria mellonella infected with C. neoformans.Mechanistic investigations showed that DSF dose-dependently inhibited the melanin, urease, acetaldehyde dehydrogenase, capsule, and biofilm formation or viability ofC. neoformans.Further study indicated DSF affectedC. neoformansby interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways included acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter) AFR2, and iron-sulfur cluster transporter ATM1. These findings contribute to the understanding of mechanisms inC. neoformans, and provide new insights for the application of DSF.
2023-12-31 | GSE248987 | GEO
Project description:Bdellovibrio bacteriovorus is a Gram-negative bacterium that is a pathogen of other Gram-negative bacteria, including many bacteria which are pathogens of humans, animals and plants. As such Bdellovibrio has potential as a biocontrol agent, or living antibiotic. B. bacteriovorus HD100 has a large genome and it is not yet known which of it encodes the molecular machinery and genetic control of predatory processes. We have tried to fill this knowledge-gap using mixtures of predator and prey mRNAs to monitor changes in Bdellovibrio gene expression at a timepoint of early-stage prey infection and prey killing in comparison to control cultures of predator and prey alone and also in comparison to Bdellovibrio growing axenically (in a prey-or host independent âHIâ manner) on artificial media containing peptone and tryptone. From this we have highlighted genes of the early predatosome with predicted roles in prey killing and digestion and have gained insights into possible regulatory mechanisms as Bdellovibrio enter and establish within the prey bdelloplast. Approximately seven percent of all Bdellovibrio genes were significantly up-regulated at 30 minutes of infection- but not in HI growth- implicating the role of these genes in prey digestion. Five percent were down-regulated significantly, implicating their role in free-swimming, attack-phase physiology. This study gives the first post- genomic insight into the predatory process and reveals some of the important genes that Bdellovibrio expresses inside the prey bacterium during the initial attack. Keywords: Transcriptional analysis 3 replicates of attack phase cells and 3 replicates of 30 minutes post-infection cells were analysed on individual arrays. Replicate 3 was normalized separately.
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2016-06-01 | E-GEOD-82060 | biostudies-arrayexpress
Project description:Candidiasis, aspergillosis, and mucormycosis cause the majority of nosocomial fungal infections in immunocompromised patients. Using an unbiased transcriptional profiling in PBMCs exposed to the fungal species causing these infections, we found a core host response in healthy individuals that governs effective fungal clearance: it consists of 156 transcripts, involving canonical and non-canonical immune pathways. Systematic investigation of key steps in antifungal host defense revealed fungal-specific signatures. As previously demonstrated, C. albicans induced interferon-related pathways. In contrast, PRRs, ROS production and host glycolytic pathways were down-regulated in response to R. oryzae, and their modulation is associated with ER-stress response. TLR5 was surprisingly identified to be uniquely regulated by A. fumigatus and to control its-induced cytokine release. In conclusion, our data reveals the transcriptional profiles induced by C. albicans, A. fumigatus, and R. oryzae, and describes both the common and specific antifungal host responses that could be exploited for novel therapeutic strategies.
2021-01-31 | GSE162746 | GEO