DNA hyper-methylation during Tuberculosis dampens host immune responsiveness
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ABSTRACT:
PROVIDER: PRJNA607988 | ENA |
REPOSITORIES: ENA
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Project description:DNA Methylation was analyzed in tuberculosis patients without HIV at baseline and 6 months after completion of successful therapy. DNA methylation was also evaluated in TB patients with HIV and in healthy controls without Tuberculosis. 500ng of gDNA was bisulfite treated prior to running the Illumina Infinium MethylEPIC array
2021-07-16 | GSE145714 | GEO
Project description:Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited. Perturbation of host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, lymphocytic choriomeningitis virus (LCMV), and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of patients with tuberculosis (TB) and their asymptomatic household contacts and found that the patients with TB have DNA hypermethylation of the IL-2/STAT5, TNF/NF-κB, and IFN-γ signaling pathways. We performed methylation-sensitive restriction enzyme-quantitative PCR (MSRE-qPCR) and observed that multiple genes of the IL-12/IFN-γ signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1, and JAK2) were hypermethylated in patients with TB. The DNA hypermethylation of these pathways was associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-γ, TNF, IL-6, CXCL9, CXCL10, and IL-1β production. The DNA hypermethylation of the IL-12/IFN-γ pathway was associated with decreased IFN-γ-induced gene expression and decreased IL-12-inducible upregulation of IFN-γ. This study demonstrates that immune cells from patients with TB are characterized by DNA hypermethylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and nonspecific immune responsiveness.
| S-EPMC7260034 | biostudies-literature
Project description:Innate immune stimulation of whole blood reveals IFN-1 hyper-responsiveness in type 1 diabetes
| PRJNA610180 | ENA
Project description:Selective stimulation of IL-4 receptor on smooth muscle induces airway hyper-responsiveness in mice. Abstract: Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse vs. human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient, but not necessary, to induce AHR and show that 5 genes known to promote smooth muscle migration, proliferation and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle-directed asthma therapeutics.
2011-01-07 | GSE26476 | GEO
Project description:Selective stimulation of IL-4 receptor on smooth muscle induces airway hyper-responsiveness in mice. Abstract: Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse vs. human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient, but not necessary, to induce AHR and show that 5 genes known to promote smooth muscle migration, proliferation and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle-directed asthma therapeutics. For the microarray aspect of of the study, there were three groups of mice: 1. IL4R gene knockout (KO) mice 2. WT mice 3. IL4R KO mice that were also transgenic for a gene construct that expressed IL4R under the control of the smooth muscle-specific promoter from the SMP8 gene All mice were subjected to intratracheal IL13 exposure for 7 days, and whole lung RNA was prepared for microarray analysis 24 hours after the last instillation. Per treatment and genotype: Two RNA pools were made from four mice each. These were labeled and hybridized to make a total of 6 microarrays. RNA was labeled with the standard Affymetrix 3' labeling protocol to make cDNA that was hybridized to Mouse MOE 430 plus 2.0 GeneChips. Gene transcripts were identified that differed in their relative expression as a function of IL4R expression on the smooth muscle cells.
2011-01-07 | E-GEOD-26476 | biostudies-arrayexpress
Project description:Gene expression analysis of Der p 1-treated mouse lungs. We developed a new mouse model of allergic airway disease employing the house dust mite allergen Der p 1. This model produces qualitatively and quantitatively different effects in two commonly used inbred strains of mice, C57BL/6J and BALB/cJ, demonstrating that genetic background is an important determinant of response to Der p 1. To identify the genes and pathways associated with inflammation and pathophysiology, we used microarrays and found genes that were shared by both strains or were distinct. Among the latter, we identified three G-protein coupled receptors and a number of other genes and pathways whose expression patterns clearly distinguish the divergent physiologic responses of the two strains. We conclude that genetic background is a strong determinant of the type and intensity of response to Der p 1, including the degree of airway hyper-responsiveness and/or inflammation. We analyzed whole lung RNAs from control (n=10-12) and Der p 1 treated (n=12-14) mice of two strains (BALB/cJ and C57BL/6J) using the Affymetrix Mouse Exon 1.0 ST platform. Array data was processed using Partek Genomics Suite software. Three techinical replicates were performed on a subset of samples.
2010-11-30 | E-GEOD-19223 | biostudies-arrayexpress
Project description:Gene expression analysis of Der p 1-treated mouse lungs. We developed a new mouse model of allergic airway disease employing the house dust mite allergen Der p 1. This model produces qualitatively and quantitatively different effects in two commonly used inbred strains of mice, C57BL/6J and BALB/cJ, demonstrating that genetic background is an important determinant of response to Der p 1. To identify the genes and pathways associated with inflammation and pathophysiology, we used microarrays and found genes that were shared by both strains or were distinct. Among the latter, we identified three G-protein coupled receptors and a number of other genes and pathways whose expression patterns clearly distinguish the divergent physiologic responses of the two strains. We conclude that genetic background is a strong determinant of the type and intensity of response to Der p 1, including the degree of airway hyper-responsiveness and/or inflammation.
2010-11-30 | GSE19223 | GEO
Project description:Chronic hepatitis C virus (HCV) infection is a leading cause of liver cancer. HCV propagation and oncogenicity depend in part on the phosphorylation states of its non-structural protein 5A (NS5A); however, little is known about how hypo- or hyper-phosphorylated NS5A functions. Here, we segregated hypo- from hyper-phosphorylated NS5A in HCV-infected Huh7.5.1 cells with two custom-made specific antibodies and differentiated their interacting proteins with dimethyl labeling-based quantitative proteomics. Bioinformatics analysis revealed that hyper-phosphorylated NS5A preferentially binds the polymerase II-associated factor 1 complex known to alter host gene expression involved in cancer progression. In contrast, hypo-phosphorylated NS5A binds proteins involved in host antiviral response. Moreover, we found that the hypo-phosphorylated NS5A binds DNA-dependent protein kinase catalytic subunit (DNA-PKcs) predicted to phosphorylate NS5A at serine 232, a key amino acid that governs NS5A transition from hypo- to hyper-phosphorylation state. Inhibition of DNA-PKcs with an inhibitor or via gene-specific knockdown significantly reduced serine 232 phosphorylation and NS5A hyper-phosphorylation. Collectively, we have identified a protein kinase that regulates a delicate balance of NS5A between hypo- and hyper-phosphorylation states respectively involved in host antiviral responses and liver cancer progression.
2019-06-17 | PXD012767 | Pride
Project description:Targeting glycolysis reduces infection and dampens inflammation in a host-directed therapy for dengue
| PRJNA719071 | ENA
Project description:Multi-omics profiling reveals the interactions of host defense and hyper-keratinization in psoriasis
| PRJNA772258 | ENA