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GSE85342
Caenorhabditis elegans
6 Downloadable Samples
Affymetrix C. elegans Genome Array (celegans)
Description
Pseudomonas aeruginosa is an opportunistic pathogen that causes severe health problems. Despite intensive investigation, many aspects of microbial virulence remain poorly understood. We used a high-throughput, high-content, whole-organism, phenotypic screen to identify small molecules that inhibit P. aeruginosa virulence in C. elegans. Approximately half of the hits were known antimicrobials. A large number of hits were non-antimicrobial bioactive compounds, including the cancer chemotherapeutic 5-fluorouracil. We determined that 5-fluorouracil both transiently inhibits bacterial growth and reduces pyoverdine biosynthesis. Pyoverdine is a siderophore that regulates the expression of several virulence determinants and is critical for pathogenesis in mammals. We show that 5-fluorouridine, a downstream metabolite of 5-fluorouracil, is responsible for inhibiting pyoverdine biosynthesis. We also show that 5-fluorouridine, in contrast to 5-fluorouracil, is a genuine anti-virulent compound, with no bacteriostatic or bacteriocidal activity. To our knowledge, this is the first report utilizing a whole-organism screen to identify novel compounds with antivirulent properties effective against P. aeruginosa.
Publication Title
A High-Content, Phenotypic Screen Identifies Fluorouridine as an Inhibitor of Pyoverdine Biosynthesis and Pseudomonas aeruginosa Virulence.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Caenorhabditis elegans
- 9 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
Pseudomonas aeruginosa is a re-emerging opportunistic pathogen with broad antimicrobial resistance. We have previously reported that the major siderophore pyoverdine from this pathogen disrupts mitochondrial networks and induces a lethal hypoxic response in model host Caernorhabditis elegans. However, the mechanism of such cytotoxicity remained unclear. Here, we demonstrate that pyoverdine translocates into host cells, binding to host ferric iron sources. The reduction of host iron content disrupts mitochondrial function such as NADH oxidation and ATP production and activates mitophagy. This activates a specific immune response that is distinct from colonization-based pathogensis and exposure to downstream pyoverdine effector Exotoxin A. Host response to pyoverdine resembles that of a hypoxic crisis or iron chelator treatment. Furthermore, we demonstrate that pyoverdine is a crucial virulence factor in P. aerguinosa pathogenesis against cystic fibrosis patients; F508 mutation in human CFTR increases susceptibility to pyoverdine-mediated damage.
Publication Title
Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 36 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Dietary methanol regulates human gene activity.
Sample Metadata Fields
Sex, Age, Specimen part, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Methanol (MeOH) is considered to be a poison in humans because of the alcohol dehydrogenase (ADH)-mediated conversion of MeOH into toxic formaldehyde (FA). Our recent genome-wide analysis of the mouse brain demonstrated that an increase in endogenous MeOH after ADH inhibition led to a significant increase in the plasma MeOH concentration and the modification of mRNA synthesis. These findings suggest endogenous MeOH involvement in homeostasis regulation by controlling mRNA levels. Here, we demonstrate directly that study volunteers displayed increasing concentrations of MeOH and FA in their blood plasma when consuming citrus pectin, ethanol and red wine. A microarray analysis of white blood cells (WBC) in volunteers after pectin intake showed various responses for 30 differentially regulated mRNAs. Most of the mRNAs were somehow involved in the pathogenesis of Alzheimer's disease (AD). There was also a decreased synthesis of hemoglobin mRNA, HBA and HBB, the presence of which in WBC RNA was not a result of red blood cells contamination because erythrocyte-specific marker genes did not show significant change. A qRT-PCR analysis of volunteer WBC after pectin and red wine intake confirmed the complicated dependence between plasma MeOH content and the mRNA accumulation of previously identified genes, namely GAPDH and SNX27, and MME, SORL1, DDIT4, HBA and HBB genes revealed in this study. We hypothesized that human plasma MeOH, which is replenished from endogenous and exogenous sources (diet), has an impact on the WBC mRNA levels of genes involved in AD pathogenesis and signaling.
Publication Title
Dietary methanol regulates human gene activity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Methanol (MeOH) is considered to be a poison in humans because of the alcohol dehydrogenase (ADH)-mediated conversion of MeOH into toxic formaldehyde (FA). Our recent genome-wide analysis of the mouse brain demonstrated that an increase in endogenous MeOH after ADH inhibition led to a significant increase in the plasma MeOH concentration and the modification of mRNA synthesis. These findings suggest endogenous MeOH involvement in homeostasis regulation by controlling mRNA levels. Here, we demonstrate directly that study volunteers displayed increasing concentrations of MeOH and FA in their blood plasma when consuming citrus pectin, ethanol and red wine. A microarray analysis of white blood cells (WBC) in volunteers after pectin intake showed various responses for 30 differentially regulated mRNAs. Most of the mRNAs were somehow involved in the pathogenesis of Alzheimer's disease (AD). There was also a decreased synthesis of hemoglobin mRNA, HBA and HBB, the presence of which in WBC RNA was not a result of red blood cells contamination because erythrocyte-specific marker genes did not show significant change. A qRT-PCR analysis of volunteer WBC after pectin and red wine intake confirmed the complicated dependence between plasma MeOH content and the mRNA accumulation of previously identified genes, namely GAPDH and SNX27, and MME, SORL1, DDIT4, HBA and HBB genes revealed in this study. We hypothesized that human plasma MeOH, which is replenished from endogenous and exogenous sources (diet), has an impact on the WBC mRNA levels of genes involved in AD pathogenesis and signaling.
Publication Title
Dietary methanol regulates human gene activity.
Sample Metadata Fields
Sex, Age, Specimen part, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Methanol (MeOH) is considered to be a poison in humans because of the alcohol dehydrogenase (ADH)-mediated conversion of MeOH into toxic formaldehyde (FA). Our recent genome-wide analysis of the mouse brain demonstrated that an increase in endogenous MeOH after ADH inhibition led to a significant increase in the plasma MeOH concentration and the modification of mRNA synthesis. These findings suggest endogenous MeOH involvement in homeostasis regulation by controlling mRNA levels. Here, we demonstrate directly that study volunteers displayed increasing concentrations of MeOH and FA in their blood plasma when consuming citrus pectin, ethanol and red wine. A microarray analysis of white blood cells (WBC) in volunteers after pectin intake showed various responses for 30 differentially regulated mRNAs. Most of the mRNAs were somehow involved in the pathogenesis of Alzheimer's disease (AD). There was also a decreased synthesis of hemoglobin mRNA, HBA and HBB, the presence of which in WBC RNA was not a result of red blood cells contamination because erythrocyte-specific marker genes did not show significant change. A qRT-PCR analysis of volunteer WBC after pectin and red wine intake confirmed the complicated dependence between plasma MeOH content and the mRNA accumulation of previously identified genes, namely GAPDH and SNX27, and MME, SORL1, DDIT4, HBA and HBB genes revealed in this study. We hypothesized that human plasma MeOH, which is replenished from endogenous and exogenous sources (diet), has an impact on the WBC mRNA levels of genes involved in AD pathogenesis and signaling.
Publication Title
Dietary methanol regulates human gene activity.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Caenorhabditis elegans
- 21 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
In the arms race of bacterial pathogenesis, bacteria produce an array of toxins and virulence factors that disrupt host processes while hosts respond with immune countermeasures. One key virulence mediator of the ubiquitous, opportunistic, extracellular pathogen Pseudomonas aeruginosa is the iron-binding siderophore pyoverdin (PMID:10722571;PMID: 8550201). The mechanisms used by pyoverdin to acquire iron from the host remain incompletely elucidated. Here we demonstrate that mitochondria represent an important target for iron acquisition and that exposure to this toxin results in loss of mitochondrial membrane potential, altered mitochondrial dynamics, and mitophagy in both Caenorhabditis elegans and mammalian cells. We also show that animal mitophagy protects the consequences of siderophore activity, conferring resistance to pyoverdin-mediated host killing. In C. elegans, the conserved autophagic genes bec-1/BECN1 and lgg-1/LC3, and the mitophagic regulator pink-1/PINK1 are required for iron chelator-elicited mitochondrial turnover and provide protection against iron sequestration by P. aeruginosa, likely by ameliorating the mitochondrial damage. While autophagic mechanisms have been implicated in the destruction of intracellular bacteria via a process called xenophagy (PMID: 24005326), our findings represent the first report of resistance to an extracellular pathogen being conferred by authentic autophagic activity that targets host organelles.
Publication Title
A conserved mitochondrial surveillance pathway is required for defense against Pseudomonas aeruginosa.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Caenorhabditis elegans
- 18 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
LIN-35 is the single C. elegans ortholog of the mammalian pocket protein family members, pRb, p107, and p130. To gain insight into the roles of pocket proteins during development, a microarray analysis was performed with lin-35 mutants. Stage-specific regulation patterns were revealed, indicating that LIN-35 plays diverse roles at distinct developmental stages. LIN-35 was found to repress the expression of many genes involved in cell proliferation in larvae, an activity that is carried out in conjunction with E2F. In addition, LIN-35 was found to regulate neuronal genes during embryogenesis and targets of the intestinal-specific GATA transcription factor, ELT-2, at multiple developmental stages. Additional findings suggest that LIN-35 functions in cell cycle regulation in embryos in a manner that is independent of E2F. A comparison of LIN-35-regulated genes with known fly and mammalian pocket-protein targets revealed a high degree of overlap, indicating strong conservation of pocket protein functions in diverse phyla. Based on microarray results and our refinement of the C. elegans E2F consensus sequence, we were able to generate a comprehensive list of putative E2F-regulated genes in C. elegans. These results implicate a large number of genes previously unconnected to cell cycle control as having potential roles in this process.
Publication Title
Transcriptome profiling of the C. elegans Rb ortholog reveals diverse developmental roles.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
Our slr-2 dataset showed strong overrepresentation of genes previously identified in a serial analysis of gene expression (SAGE) intestinal library (McGhee et al., 2006) (p << 0.01); 812 genes were common to both data sets. Consistent with the deregulation of intestinal genes, we observed repression of several important metabolic pathways, including the TOR and insulin signaling networks, suggesting that slr-2(ku297) mutants experience metabolic stress. We also compared differentially regulated genes in slr-2 and lin-35 single mutants. Again, we saw a statistically significant overlap (p-value < 0.01); 261 genes were present in both data sets. Strikingly, > 75% of genes common both datasets showed expression changes in the same direction, although the common dataset contained an approximately equal mixture of up and downregulated genes. Furthermore, more than fifty genes common to the lin-35 and slr-2 datasets are known to have intestinal-associated functions. That some of these common intestinal genes were absent from the gut SAGE library could be due to differences in the developmental stage of the animals assayed (adults versus L1s) as well as experimental approaches (SAGE versus microarrays)
Publication Title
Coordinated regulation of intestinal functions in C. elegans by LIN-35/Rb and SLR-2.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
The nematode Caenorhabditis elegans offers currently untapped potential for carrying out high-throughput, live-animal screens of low molecular weight compound libraries to identify molecules that target a variety of cellular processes. We previously used a bacterial infection assay in C. elegans to identify 119 compounds that affect host-microbe interactions among 37,214 tested. We subsequently found that one of these small molecules, RPW-24, protects C. elegans from bacterial infection by stimulating the host immune response of the nematode. Using transcriptome profiling, epistasis pathway analyses with C. elegans mutants, and an RNAi screen, we showed that RPW-24 promotes resistance to Pseudomonas aeruginosa infection by inducing the transcription of a remarkably small number of C. elegans genes (~1.3% of all genes) in a manner that partially depends on the evolutionarily-conserved p38 MAP kinase pathway and the transcription factor ATF-7. These data demonstrated that the immunostimulatory activity of RPW-24 is required for its efficacy and define a novel C. elegans-based strategy to identify compounds with activity against antibiotic-resistant bacterial pathogens. Here we present the microarray data that were used to define the genes that are differentially regulated in wild-type nematodes following exposure to RPW-24.
Publication Title
Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection.
Sample Metadata Fields
Specimen part, Treatment
View Samples