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SRP140558
Homo sapiens
62 Downloadable Samples
Illumina HiSeq 2500
Description
Background: A subset of infants are hyper-susceptible to severe/acute viral bronchiolitis (AVB), for reasons unknown. Purpose: To characterise the cellular/molecular mechanisms underlying infant AVB in circulating cells/local airways tissues. Methods: PBMC and nasal mucosal scrapings (NMS) were obtained from Infants (<18mths) and children (1.5-5yrs) during AVB and post-convalescence. Immune response patterns were profiled by multiplex analysis of plasma cytokines, flow cytometry, and transcriptomics (RNA-Seq). Molecular profiling of group-level data utilised a combination of upstream regulator and coexpression network analysis, followed by individual subject-level data analysis employing personalised N-of-1-pathways methodology. Results: Group-level analyses demonstrated that infant PBMC responses were dominated by monocyte-associated hyper-upregulated type I interferon signalling/pro-inflammatory pathways (drivers: TNF, IL6, TREM1, IL1B), versus a combination of inflammation (PTGER2, IL6) plus growth/repair/remodelling pathways (ERBB2, TGFB1, AREG, HGF) coupled with Th2 and NK-cell signalling in children. Age-related differences were not attributable to differential steroid usage or variations in underlying viral pathogens. Nasal mucosal responses were comparable qualitatively in infants/children, dominated by interferon types I-III, but the magnitude of upregulation was higher in infants (range 6-48-fold) than children (5-17-fold). N-of-1-pathways analysis confirmed differential upregulation of innate immunity in infants and NK cell networks in children, and additionally demonstrated covert AVB response sub-phenotypes that were independent of chronological age. Conclusions: Dysregulated expression of interferon-dependent pathways following respiratory viral infections is a defining immunophenotypic feature of AVB-susceptible infants and a subset of children. Susceptible subjects appear to represent a discrete subgroup who cluster based on (slow) kinetics of postnatal maturation of innate immune competence. Overall design: The study design consisted of PBMC from infants (<18months, n=15 pairs) and pre-school children (2-5yrs, n=16 pairs) sampled during severe acute viral bronchiolitis (acute visit = AV) and following recovery during convalescence (convalescent visit = CV). RNA-Seq profiles were generated by sequencing llumina HiSeq2500, 50bp single-end reads, v4 chemistry. Samples were sequenced across two lanes and collapsed prior analysis.
Publication Title
Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis.
Sample Metadata Fields
Subject
View Samples SRP140557- Homo sapiens
- 56 Downloadable Samples
- Illumina HiSeq 2500
Description
Background: A subset of infants are hyper-susceptible to severe/acute viral bronchiolitis (AVB), for reasons unknown. Purpose: To characterise the cellular/molecular mechanisms underlying infant AVB in circulating cells/local airways tissues. Methods: PBMC and nasal mucosal scrapings (NMS) were obtained from Infants (<18mths) and children (1.5-5yrs) during AVB and post-convalescence. Immune response patterns were profiled by multiplex analysis of plasma cytokines, flow cytometry, and transcriptomics (RNA-Seq). Molecular profiling of group-level data utilised a combination of upstream regulator and coexpression network analysis, followed by individual subject-level data analysis employing personalised N-of-1-pathways methodology. Results: Group-level analyses demonstrated that infant PBMC responses were dominated by monocyte-associated hyper-upregulated type I interferon signalling/pro-inflammatory pathways (drivers: TNF, IL6, TREM1, IL1B), versus a combination of inflammation (PTGER2, IL6) plus growth/repair/remodelling pathways (ERBB2, TGFB1, AREG, HGF) coupled with Th2 and NK-cell signalling in children. Age-related differences were not attributable to differential steroid usage or variations in underlying viral pathogens. Nasal mucosal responses were comparable qualitatively in infants/children, dominated by interferon types I-III, but the magnitude of upregulation was higher in infants (range 6-48-fold) than children (5-17-fold). N-of-1-pathways analysis confirmed differential upregulation of innate immunity in infants and NK cell networks in children, and additionally demonstrated covert AVB response sub-phenotypes that were independent of chronological age. Conclusions: Dysregulated expression of interferon-dependent pathways following respiratory viral infections is a defining immunophenotypic feature of AVB-susceptible infants and a subset of children. Susceptible subjects appear to represent a discrete subgroup who cluster based on (slow) kinetics of postnatal maturation of innate immune competence. Overall design: The study design consisted of PBMC from infants (<18months, n=15 pairs) and pre-school children (2-5yrs, n=16 pairs) sampled during severe acute viral bronchiolitis (acute visit = AV) and following recovery during convalescence (convalescent visit = CV). RNA-Seq profiles were generated by sequencing llumina HiSeq2500, 50bp single-end reads, v4 chemistry. Samples were sequenced across two lanes and collapsed prior analysis.
Publication Title
Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 9 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Salmonella enterica is a Gram-negative bacterium that causes gastroenteritis, bacteremia and typhoid fever in several animal species including humans. Its virulence is greatly dependent on two type III secretion systems (T3SSs), encoded in pathogenicity islands 1 (SPI1) and 2 (SPI2), respectively. These systems translocate proteins called effectors into eukaryotic host cell. Effectors interfere with certain host signal transduction pathways to allow the internalization of pathogens and their survival and proliferation inside vacuoles. SteA is one of the few Salmonella effectors that are substrates of both T3SSs. Nothing is known about the function of this protein inside the host cells. Here, we used gene arrays and bioinformatics analysis to study the genetic response of human epithelial cells to SteA. We found that constitutive synthesis of SteA in epithelial cells leads to induction of genes related to extracellular matrix organization and regulation of cell proliferation and serine/threonine kinase signaling pathways. SteA also represses genes related to immune processes and regulation of purine nucleotide synthesis and pathway-restricted SMAD protein phosphorylation. Consisted with this analysis a cell biology approach revealed that epithelial cells expressing steA show altered cell morphology, reduction of cytotoxicity, cell-cell adhesion and migration capability, and increase in endocytosis.
Publication Title
Global impact of Salmonella type III secretion effector SteA on host cells.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
The lipocalin Apolipoprotein D (ApoD), known to protect the nervous system against oxidative stress (OS) in model organisms, is up-regulated early in the mouse brain in response to the ROS generator paraquat (PQ). However, the processes triggered by this up-regulation have not been explored.
Publication Title
Apolipoprotein D alters the early transcriptional response to oxidative stress in the adult cerebellum.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
DREAM (downstream regulatory element antagonist modulator) is a Ca2+-binding protein that binds DNA and represses transcription in a Ca2+-dependent manner. Previous studies have shown a role for DREAM in cerebellar function regulating the expression of the sodium/calcium exchanger3 (NCX3) in cerebellar granules to control Ca2+ homeostasis and survival of these neurons. To achieve a more global view of the genes regulated by DREAM in the cerebellum, we performed a genome-wide analysis in transgenic cerebellum expressing a Ca2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Our results indicate that DREAM is a major transcription factor in the cerebellum that regulates genes important for cerebellar development.
Publication Title
Reduced Mid1 Expression and Delayed Neuromotor Development in daDREAM Transgenic Mice.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Cytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferases (DNMT) inhibitor which induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in G0-G1 phase and decreasing the production of proinflammatory cytokines such as TNF and IFN. This effect was not due to a pro-apoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes which induce cell growth arrest, such as DCUN1D2, U2AF2, GADD45B or p53. In spite of being also up-regulated, we did not find any effect of 5-azaC on the methylation pattern of FOXP3. Finally, the administration of 5-azaC at 60 and 84 hours post-transplant prevented the development of GVHD leading to a significant increase in survival in a fully mismatched BMT mouse model. In conclusion, the current study shows the effect of 5-azaC in T-lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways which must be explored in order to prevent graft-versus-host disease.
Publication Title
Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Homo sapiens
- 74 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal migr-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system.
Publication Title
Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes.
Sample Metadata Fields
Subject, Time
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
bulk RNAseq of MUC1 kidney disease patient derived kidney epithelial cells compare to normal kidney cells. The goal of this study was to elucidate the biological mechanism underlying MUC1 kidney disease using MUC1 expressing cells derived from either a patient or a healthy individual kidney Overall design: Bulk RNAseq of immortalized patient compare to normal cell line
Publication Title
Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 27 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Atopic dermatitis (AD) is a common inflammatory skin disease with a T(H)2 and T22 immune polarity. Despite recent data showing a genetic predisposition to epidermal barrier defects in some patients, a fundamental debate still exists regarding the role of barrier abnormalities versus immune responses in initiating the disease. An extensive study of nonlesional AD (ANL) skin is necessary to explore whether there is an intrinsic predisposition to barrier abnormalities, background immune activation, or both in patients with AD. We sought to characterize ANL skin by determining whether epidermal differentiation and immune abnormalities that characterize lesional AD (AL) skin are also reflected in ANL skin. We performed genomic and histologic profiling of both ANL and AL skin lesions (n = 12 each) compared with normal human skin (n = 10). We found that ANL skin is clearly distinct from normal skin with respect to terminal differentiation and some immune abnormalities and that it has a cutaneous expansion of T cells. We also showed that ANL skin has a variable immune phenotype, which is largely determined by disease extent and severity. Whereas broad terminal differentiation abnormalities were largely similar between involved and uninvolved AD skin, perhaps accounting for the background skin phenotype, increased expression of immune-related genes was among the most obvious differences between AL and ANL skin, potentially reflecting the clinical disease phenotype. Our study implies that systemic immune activation might play a role in alteration of the normal epidermal phenotype, as suggested by the high correlation in expression of immune genes in ANL skin with the disease severity index.
Publication Title
Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We aimed to identify genes that are regulated at downstream of FGFR1/KLB receptor complex in brown adiposetissues of adult male mice on high fat diet by injecting anti-FGFR1/KLB agonisticantibody or human FGF21.
Publication Title
Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex.
Sample Metadata Fields
Specimen part
View Samples