Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Genome-wide expression analysis of the effects of a parasitic nematode's secreted exosomes on mammalian cells.

ABSTRACT: We show that a gastrointestinal nematode that infects mice, Heligmosomoides polygyrus, secretes vesicles packaged with specific microRNAs (miRNAs) and Y RNAs as well as a nematode-specific Argonaute protein. The vesicles are of intestinal origin and are enriched for homologs of mammalian proteins found in exosomes, including heat shock proteins, tetraspanins and an ESCORT protein. The nematode-derived vesicles are internalized by mouse intestinal epithelial cells and mediate changes in expression of host genes involved in inflammation and immunity, including the receptor for the alarmin IL33 as well as a key regulator of MAPK signaling, DUSP1. A total of 12 samples were analyzed, from 4 different conditions: medium, exosome-treated, LPS and LPS+exosomes, each with 3 biological replicates. One of the 'medium' replicates was discarded due to outlier behaviour.

ORGANISM(S): Mus musculus

SUBMITTER: Cei Abreu-Goodger

PROVIDER: E-GEOD-55941 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity.

Buck Amy H AH Coakley Gillian G Simbari Fabio F McSorley Henry J HJ Quintana Juan F JF Le Bihan Thierry T Kumar Sujai S Abreu-Goodger Cei C Lear Marissa M Harcus Yvonne Y Ceroni Alessandro A Babayan Simon A SA Blaxter Mark M Ivens Alasdair A Maizels Rick M RM

Nature communications 20141125

In mammalian systems RNA can move between cells via vesicles. Here we demonstrate that the gastrointestinal nematode Heligmosomoides polygyrus, which infects mice, secretes vesicles containing microRNAs (miRNAs) and Y RNAs as well as a nematode Argonaute protein. These vesicles are of intestinal origin and are enriched for homologues of mammalian exosome proteins. Administration of the nematode exosomes to mice suppresses Type 2 innate responses and eosinophilia induced by the allergen Alternari ...[more]

PMID: 25421927

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Project description:The function of human circulating proangiogenic cells (PACs) has been described extensively. However, little focus has been placed on understanding how these cells differ in their functions in the presence of microenvironments mimicking vascular inflammation. We hypothesized that exposure to proinflammatory cytokines or the oxLDL, an autoantigen abundant in advanced atherosclerotic plaques, converts PACs into immune-modulating/proinflammatory cells. Hence, we examined the effect of oxLDL and inflammatory stimuli on their phenotype by use of a functional genomics model based on secretome and whole genome transcriptome profiling. PACs obtained from culturing a PBMC fraction in angiogenic medium were primed with DC differentiation cytokines for 3 days and then exposed to proinflammatory cytokines or oxLDL for 2 days. Under these conditions, PACs converted into APCs (APCcy and APCox, respectively), expressed maturation markers CD80 and CD83, and showed an up-regulation of CD86. APCcy and APCox induced a robust T cell BrdU incorporation. Despite a similar ability to induce lymphocyte proliferation, APCcy and APCox differed for the secretory pathway and mRNA expression. Analysis of the differentially expressed genes identified 4 gene "clusters", showing reciprocal modulation in APCcy vs. APCox justifying, according to functional genomics analyses, a different putative function of the cells in antigen processing. Together, these data show that treatment with inflammatory cytokines or oxLDL converts human PAC phenotype and function into that of APCs with similar lymphocyte-activating ability but distinct maturation degree and paracrine functions. PBMC-derived PACs were committed with GM-CSF and IL-4 to a dendritic phenotype, and then exposed to proinflammatory cytokines (IL-1β and TNF-α) or to the oxidized form of LDL (oxLDL). Functional assays and whole genome gene expression profiling were performed both on PACs (n=6) and or resulting cytokine- (APCcy, n=6) and oxLDL-induced APCs (APCox, n=6). RNA was reverse transcribed, labeled, and linearly amplified, and then hybridized to HumanHT-12 v.4 Expression BeadChip microarrays. To estimate technical variability, ≈20% of the samples (n=4) were hybridized in duplicate.

Project description:Non-invasive or minimally invasive surrogate approaches to detect/predict target organ toxicity have significant practical applications in occupational toxicology. Presently, using a rat model, we have investigated the potential application of peripheral blood transcriptomics as a practical approach to study the mechanisms of silica-induced pulmonary toxicity. Rats were exposed by inhalation to crystalline silica for one week (15 mg/m3, 6-hours/day, 5 days/week). Pulmonary toxicity and global gene expression profiles of lungs and peripheral blood were determined in the control and silica exposed rats at 32-weeks following termination of silica exposure. A significant elevation in bronchoalveolar lavage fluid (BALF) lactate dehydrogenase (LDH) activity and moderate histological changes in the lungs, including type II pneumocyte hyperplasia and fibrosis, indicated silica-induced pulmonary toxicity in the rats. Similarly, significant infiltration of neutrophils and elevated monocyte chemotactic protein-1 (MCP1) level in the lungs suggested silica-induced pulmonary inflammation in the rats. Microarray analysis of global gene expression profiles identified significant differential expression (>1.5 fold change and FDR p<0.01) of 520 and 537 genes, respectively, in the lungs and blood of the silica exposed rats. Bioinformatics analysis of the differentially expressed genes demonstrated significant similarity in the biological processes, molecular networks, and canonical pathways enriched by silica exposure in the lungs and blood of the rats. Several genes involved in functions relevant to silica-induced pulmonary toxicity such as inflammation, respiratory diseases, cancer, cellular movement, fibrosis, etc, were found significantly differentially expressed in the lungs and blood of the silica exposed rats. The results of this study, in addition to providing molecular insights into the mechanisms underlying silica-induced pulmonary toxicity, suggested the potential application of peripheral blood gene expression profiling as a toxicologically relevant and minimally invasive surrogate approach to study the mechanisms underlying silica-induced pulmonary toxicity. Non-invasive or minimally invasive surrogate approaches to detect/predict target organ toxicity have significant practical applications in occupational toxicology. Presently, using a rat model, we have investigated the potential application of peripheral blood transcriptomics as a practical approach to study the mechanisms of silica-induced pulmonary toxicity. Rats were exposed by inhalation to crystalline silica for one week (15 mg/m3, 6-hours/day, 5 days/week). Pulmonary toxicity and global gene expression profiles of lungs and peripheral blood were determined in the control and silica exposed rats at 32-weeks following termination of silica exposure. A significant elevation in bronchoalveolar lavage fluid (BALF) lactate dehydrogenase (LDH) activity and moderate histological changes in the lungs, including type II pneumocyte hyperplasia and fibrosis, indicated silica-induced pulmonary toxicity in the rats. Similarly, significant infiltration of neutrophils and elevated monocyte chemotactic protein-1 (MCP1) level in the lungs suggested silica-induced pulmonary inflammation in the rats. Microarray analysis of global gene expression profiles identified significant differential expression (>1.5 fold change and FDR p<0.01) of 520 and 537 genes, respectively, in the lungs and blood of the silica exposed rats. Bioinformatics analysis of the differentially expressed genes demonstrated significant similarity in the biological processes, molecular networks, and canonical pathways enriched by silica exposure in the lungs and blood of the rats. Several genes involved in functions relevant to silica-induced pulmonary toxicity such as inflammation, respiratory diseases, cancer, cellular movement, fibrosis, etc, were found significantly differentially expressed in the lungs and blood of the silica exposed rats. The results of this study, in addition to providing molecular insights into the mechanisms underlying silica-induced pulmonary toxicity, suggested the potential application of peripheral blood gene expression profiling as a toxicologically relevant and minimally invasive surrogate approach to study the mechanisms underlying silica-induced pulmonary toxicity. A total of 12 rat blood samples were analyzed in this gene expression experiment. Rats were exposed to crystalline silica at a concentration of 15 mg/m3, 6-hours/day for 5 consecutive days. Rats exposed simultaneously to filtered air served as the controls. The control (n=6) and silica exposed (n=6) rats were sacrificed at post-exposure time interval of 32 weeks following termination of silica exposure and blood gene expression profiles were determined.

Dataset Information

Genome-wide expression analysis of the effects of a parasitic nematode's secreted exosomes on mammalian cells.

Publications

Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity.

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