Gaucher Disease Renders Resistance Against Viral Infection of the CNS
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ABSTRACT:
PROVIDER: PRJNA597149 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10753158.fastq.gz | Fastqsanger.gz | |||
| SRR10753159.fastq.gz | Fastqsanger.gz | |||
| SRR10753160.fastq.gz | Fastqsanger.gz | |||
| SRR10753161.fastq.gz | Fastqsanger.gz | |||
| SRR10753162.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: In order to describe how non- genetic factors may contribute to emergence of additional neurodegenerative disorders in mice with neuronal Gaucher Disease (nGD), full transcript mRNA sequencing was implemented with half brain in order to study differential gene expression between experimental groups: (Untreated) Control, CBE (Conduritol β epoxide ), SVNI (Sindbis virus), and CBE + SVNI Methods: Full transcript mRNA sequencing was implemented with half brain in order to study differential gene expression between experimental groups (biologilal triplicates in each group). We mapped 20 million sequence reads per sample to the mouse genome (GRCm38) and identified 16,903 transcripts. . All subjects were 28 days old. Half of the bisected brains were flash-frozen in liquid nitrogen and stored in -80C conditions until use. RNA was isolated using a RNeasy mini kit (Qiagen, Hilden, Germany). Extraction of RNA was performed at the Israeli Institute for Biological Research and the RNA was then transferred to the Weizmann Institute of Science for further analysis. Quality was examined with the Agilent 2200 TapeStation system (Agilent Technologies); RIN values of each sample were determined satisfactory for use in sequencing. Expression of mRNA was quantified using DESeq following normalization of library size with Pipeline. Gene lists were created by criteria based on an absolute linear fold change ≥ 2.0, *p ≤ 0.05. Enriched pathways in the resulting gene lists were analyzed with Ingenuity Pathway Analysis (IPA). Results: Our study represents the first full RNA transcriptome analysis of brains from of CBE-treated mice, with biological triplicates generated by RNA-seq technology. The CBE and CBE+SVNI conditions boast remarkably similar genetic profiles with no differentially expressed genes changed between them (fold change ≥ 2.0, *p ≤ 0.05). In CBE, SVNI, and CBE + SVNI conditions respectively, 501, 1724, and 554 genes were significantly upregulated compared to the control, while 5, 333, and 40 genes were significantly downregulated respectively (Fig. 2B). Surprisingly, 476 upregulated genes in the CBE condition were shared with SVNI, while only 25 genes were uniquely upregulated. No downregulated genes were shared between the two conditions (Fig. 2C). Here, we conclude that CBE and CBE+SVNI demonstrate nearly identical mRNA profiles while SVNI boasted highly differential genes compared to all other conditions. Conclusion: Half brain mRNA profiles of 28-day old untreated (Control), CBE-treated, SVNI-treated, and SVNI + CBE-treated mice were generated by deep sequencing, in triplicate, using Illumina Hiseq.
2020-08-25 | GSE142485 | GEO
Project description:Due to the vital importance of the Central Nervous System (CNS), its potential infection and inflammation have to be tightly controlled. The surface of the CNS is connected to the periphery by a rich and complex tissue, the meninges. They contain a vast network of macrophages subdivided in at least two subpopulations endowed with elusive functions: a neonatal, MHC-II negative macrophage population, and an post-natal population expressing MHC-II. Using in situ-histocytometry, flow cytometry, and single-cell RNA sequencing approaches, we showed that those populations have opposite dynamic behaviors in response to in vivo peripheral challenges such as LPS, SARS-CoV2 and lymphocytic choriomeningitis virus (LCMV), with an apparent contraction of the MHC-II+ population. Focusing on LCMV infection in experimental mouse models and using innovative pharmacological and genetic depletion strategies, we show that meningeal macrophages (MM) represent an early line of protection against this neuroinvasive pathogen. In their absence, specific areas in the meninges became highly infected, leading to fatal brain disease. While their intrinsic sensing of viral replication through the Mitochondrial antiviral-signaling protein (MAVS) was dispensable, sensing of IFNs through the STAT1 pathway played an important role in controlling viral spread. Unexpectedly, the post-natal MHC-II+ macrophage population had an important role in controlling neuroinfection, by shutting down biosynthesis pathways and efficiently blocking viral replication. This work helps understanding the spatial organization of the brain defense system and the cellular and molecular mechanisms involved in CNS protection.
2021-12-02 | GSE189887 | GEO
Project description:Gaucher disease (GD) is characterized by the presence of glucosylceramide-laden macrophages (Gaucher cells) as the result of deficiency in the lysosomal hydrolase glucocerebrosidase (GBA). Non-neuronopathic type 1 GD is effectively treated by infusions with macrophage-targeted recombinant glucocerebrosidase. We here report how LC-MSE analysis of the proteome of laser-dissected splenic Gaucher cells revealed high expression of several proteins amongst which was gpNMB. This was confirmed by histochemistry and RNA quantification. Macrophages produce gpNMB as membrane protein but release soluble fragments. In plasma of symptomatic Gaucher patients (n=59) soluble gpNMB was next found to be on average 25-fold increased prior to treatment, without overlap with control values, (control mean: 20 ng/ml; range 11-34 ng/ml vs. GD mean: 495 ng/ml; range: 137-1283 ng/ml).
2016-09-27 | PXD001598 | Pride
Project description:Gene expression data obtained from induced pluripotent stem cells derived from wild type fibroblasts (iPSc WT) and from Gaucher Disease type 2 fibroblasts (GD iPSc). Also, gene expression analysis from the initial fibroblasts was made (WT fibroblasts and GD- fibroblasts), as well as gene expression analysis from a human embryonic stem cell line (hES4). Two different iPSc cell lines derived from Gaucher Disease type 2 fibroblasts were analysed in order to be compared to iPSc derived from Wild Type fibroblasts (only one cell line) and human embryonic stem cells (only one cell line). The initial cells: two different wild type fibroblasts and one Gaucher disease type 2 fibroblasts were also analysed.
2012-12-07 | E-GEOD-41243 | biostudies-arrayexpress
Project description:Gaucher disease, a recessive inherited metabolic disorder caused by defects in the gene encoding glucosylceramidase (GlcCerase), can be divided into three subtypes according to the appearance of symptoms associated with central nervous system involvement. We now identify a protein, glycoprotein non-metastatic B (GPNMB), that acts as an authentic marker of brain pathology in neurological forms of Gaucher disease. Using three independent techniques, including quantitative global proteomic analysis of cerebrospinal fluid (CSF) in samples from Gaucher disease patients that display neurological symptoms, we demonstrate a correlation between the severity of symptoms and GPNMB levels. Moreover, GPNMB levels in the CSF correlate with disease severity in a mouse model of Gaucher disease. GPNMB was also elevated in brain samples from patients with type 2 and 3 Gaucher disease. Our data suggest that GPNMB can be used as a marker to quantify neuropathology in Gaucher disease patients and as a marker of treatment efficacy once suitable treatments towards the neurological symptoms of Gaucher disease become available.
2016-06-24 | PXD001654 | Pride
Project description:Background. The blood-brain barrier (BBB) regulates immune cell entry into the CNS, and various strategies have been developed to target this barrier in efforts to alleviate neuroinflammation in neurodegenerative diseases. α4β1 is crucial for T cell influx into the CNS. In the context of HIV, CD4 T cells drive viral infiltration, while CD8 T cells are essential for viral clearance. This dual role complicates strategies aimed at targeting T cell entry during HIV infection, yet it remains an area that has not been thoroughly explored. Methods. We investigated the impact of disrupting α4-mediated T cell entry into the CNS in SIVmac251-infected rhesus macaques treated with an α4-blocking antibody (n=4) versus an isotype control (n=4). Our comprehensive approach included single-cell analysis of CD45+ cells in the brain and spleen, spatial transcriptomics of the hippocampus, viral load measurements, and flow cytometry on brain tissue. Results. Single-cell analysis revealed a marked reduction in the brain CD8 TEM cluster, particularly in cells expressing Granulysin, CCL5, and STAT4, while CD4 T cell clusters remained unchanged, and two monocyte clusters were enriched. This shift was accompanied by an increase in brain SIV RNA+ CD45+ CD4+ T cells in the α4-treated group (vRNA+ cells = 60) compared to controls (n=11). Spatial transcriptomics of SIV vRNA+ versus SIV vRNA- regions in the hippocampus of α4-treated macaques showed enrichment of CD4 TCM and monocyte gene signatures. Correspondingly, quantitative PCR revealed higher vRNA levels in the gray matter of the PFC, STS, and Hp. These findings suggest that α4 blockade selectively disrupts CD8 TEM populations while sparing CD4 T cells, leading to elevated viral loads and heightened neuroinflammation. The increase in SIV RNA+ CD4+ T cells and viral loads in the gray matter furthermore underscores the compartmentalized effect of α4-mediated immune modulation on viral dynamics across distinct brain regions Conclusion. These results underscore the critical need to evaluate immune-targeting therapies, with implications for strategies aimed at controlling T cell influx in the context of viral infections in the brain.
2024-11-01 | GSE279903 | GEO
Project description:Barcoded viral tracing of single-cell interactions in CNS inflammation
| PRJNA633870 | ENA
Project description:This work presents the discovery of genes that are dysregulated in patients with Type I and Type III Gaucher Disease. It provides insight into the unique pathogenesis of these phenotypes, improved diagnostic accuracy and potential novel therapies for these patients. Control and patient fibroblast cultures were established from full-thickness, skin biopsies obtained under a protocol approved by the IRB of the National Institute of Neurological Disorders and Stroke. Patient cultures were homoallelic for either the N370S mutation (non-neuronopathic, Gaucher Disease Type I, n=5), the L444P mutation (neuronopathic, Gaucher Disease Type III, n=5), or Wild-Type (Control, n=4).
2010-06-08 | E-GEOD-21899 | biostudies-arrayexpress
Project description:Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela-treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks and were sacrificed one week after the injection for RNA isolation from different tissues like liver, lung and spleen.
2013-09-07 | E-GEOD-44569 | biostudies-arrayexpress
Project description:Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela- treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks. To understand the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela).
2013-09-07 | E-GEOD-44640 | biostudies-arrayexpress