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.
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Project description:Intracellular pathogens requires efficient mechanism adapting the environment inside of host cells. Here we show that the transcriptomes of the cellular mycobacterium tuberculosis and of those released from the infected macrophage cells contain a large fraction of human transcripts by RNA polymerase II. Uptake of host pre-mRNAs is coincident with the co-localization of M. tuberculosis with nuclear membrane. The infective M. tuberculosis selectively uptakes snoRNAs.The intracellular pathogens has a preferable capability in taking pre-mRNAs. The host transcripts are not generally spliced nor translated.We suggest that the intracellular bacterium has acquired a mechanism to take transcripts from the host cell nuclus as its own nutrient supply and may help them to survive with hosts.
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2016-03-01 | GSE78706 | 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.
2011-01-07 | GSE26476 | GEO
Project description:Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global health threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a complementing strategy for infection treatment through targeting host immune mechanisms. However, the limited understanding of the host factors and their regulatory mechanisms involved in host immune defense against infections has impeded HDT development. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) elicits host protective immunity against Mtb. Mechanistically, TRIM27 enters host cell nucleus upon Mtb infection to function as a transcription activator of transcription factor EB (TFEB). TRIM27 binds to TFEB promoter and the TFEB transcription factor cAMP responsive element binding protein 1 (CREB1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity towards TFEB, eventually leading to autophagy activation and pathogen clearance. Thus, TRIM27 contributes to host anti-Mtb immunity and targeting TRIM27/CREB1/TFEB axis serves as a promising HDT-based TB treatment.
2024-07-03 | GSE237039 | GEO
Project description:The factors that determine the outcome of clinical tuberculosis lie within both the host and the pathogen, Mycobacterium tuberculosis (Mtb). The advent of recombinant inbred mouse panels and next-generation transposon mutagenesis and sequencing approaches has enabled dissection of the host-pathogen interface for mammalian and pathogen genetic determinants of disease outcome. To identify host and pathogen genetic drivers of Mtb infection, we infected 19 genotypes from the BXD panel, bred from Mtb-resistant C57BL/6J (B6) and Mtb-susceptible DBA/2J (D2), with a comprehensive library of transposon mutants (TnSeq). The survival of each of the ~4000 bacterial mutants within each distinct host was quantified and leveraged as refined “endophenotypes”, directly reporting on the infection microenvironment. We leveraged QTL mapping to associate each varying bacterial fitness endophenotype to the host genome and identified 140 significant host-pathogen quantitative trait loci (hpQTL). This host-pathogen interaction screen reinforces the utility of bacterial mutant libraries as precise reporters of host immunological microenvironment during infection and highlights host gene candidates for further investigation.
2023-06-07 | GSE234093 | GEO
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. 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