Early secreted antigenic target of 6-kDa of Mycobacterium tuberculosis induces transition of macrophages into epithelioid macrophages by downregulating iNOS / NO-mediated H3K27 trimethylation in macrophages
“…H37Ra infected macrophages. Previous studies have shown that lincRNACox2 increased significantly in TB patients and cox2 and inoS were also promoted (15,16), so the function of lincrnacox2 in an in vitro cell experiment was assessed. In vitro cell experiments, rT-qPcr and western blotting were performed to assess the expression level of lincrnacox2 in macrophages after exposure to H37ra.…”
Section: Expression Of Lincrnacox2 and Inflammatory Responses Inmentioning
long intergenic non-coding rnas (lincrnas) are long non-coding transcripts from the intergenic regions of annotated protein-coding genes. lincrna cyclooxygenase 2 (cox2) is an early-primary response gene regulated by the nF-κB signaling pathway in macrophages. it was found that lincRNACox2 was significantly increased in patients with the Mycobacterium tuberculosis (M. tuberculosis) H37ra strain infection and macrophages, using reverse transcription-quantitative Pcr (rT-qPcr). eliSa, western blotting and rT-qPcr results indicated that the inflammatory response factors tumor necrosis factor-α, interferon-γ, interleukin-6, cox2 and inducible nitric oxide synthase were significantly increased in H37Ra infected macrophages. In addition, the inflammatory regulating proteins nF-κB and Stat3 were significantly increased in H37ra infected macrophages but decreased in lincrnacox2 knockdown macrophages infected with H37ra. Moreover, the knockdown of lincrnacox2 increased the apoptotic rate of H37ra infected macrophages and facilitated the proliferation of H37ra. collectively, the present results suggested that lincrnacox2 may be required for the activation of nF-κB and Stat3, in order to regulate inflammatory responses involved in resistance to M. tuberculosis infection.
“…H37Ra infected macrophages. Previous studies have shown that lincRNACox2 increased significantly in TB patients and cox2 and inoS were also promoted (15,16), so the function of lincrnacox2 in an in vitro cell experiment was assessed. In vitro cell experiments, rT-qPcr and western blotting were performed to assess the expression level of lincrnacox2 in macrophages after exposure to H37ra.…”
Section: Expression Of Lincrnacox2 and Inflammatory Responses Inmentioning
long intergenic non-coding rnas (lincrnas) are long non-coding transcripts from the intergenic regions of annotated protein-coding genes. lincrna cyclooxygenase 2 (cox2) is an early-primary response gene regulated by the nF-κB signaling pathway in macrophages. it was found that lincRNACox2 was significantly increased in patients with the Mycobacterium tuberculosis (M. tuberculosis) H37ra strain infection and macrophages, using reverse transcription-quantitative Pcr (rT-qPcr). eliSa, western blotting and rT-qPcr results indicated that the inflammatory response factors tumor necrosis factor-α, interferon-γ, interleukin-6, cox2 and inducible nitric oxide synthase were significantly increased in H37Ra infected macrophages. In addition, the inflammatory regulating proteins nF-κB and Stat3 were significantly increased in H37ra infected macrophages but decreased in lincrnacox2 knockdown macrophages infected with H37ra. Moreover, the knockdown of lincrnacox2 increased the apoptotic rate of H37ra infected macrophages and facilitated the proliferation of H37ra. collectively, the present results suggested that lincrnacox2 may be required for the activation of nF-κB and Stat3, in order to regulate inflammatory responses involved in resistance to M. tuberculosis infection.
“…Gene loci associated with enriched GWAS SNPs for the CHA breed group also included the CILK1 gene (aka ICK ) and the Kelch repeat and BTB domain containing 3 gene ( KCNJ15 ), which has been detected as an expression biomarker for human TB [ 69 ]; the T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 gene ( TCIRG1 ), a known antimycobacterial host defence gene that has been shown to be a key hub gene associated with IFN-γ stimulation of human macrophages [ 70 ]; and the Von Willebrand factor gene ( VWF ). Notable gene loci associated with enriched GWAS SNPs for the Limousin breed group included the cellular repressor of E1A stimulated genes 1 gene ( CREG1 ), which encodes a regulator of core macrophage differentiation genes [ 71 ]; the desmoplakin gene ( DSP ), which increases in expression during M. tuberculosis -derived ESAT6-regulated transition of bone marrow-derived macrophages (BMDMs) into epithelioid macrophages [ 72 ]; and the SP110 nuclear body protein gene ( SP110 ), which encodes a protein that modulates growth of MTBC pathogens in macrophages and has been successfully exploited for genome editing of cattle to enhance resistance to M. bovis infection [ 73 ]. Fig.…”
Background
Bovine TB (bTB), caused by infection with Mycobacterium bovis, is a major endemic disease affecting global cattle production. The key innate immune cell that first encounters the pathogen is the alveolar macrophage, previously shown to be substantially reprogrammed during intracellular infection by the pathogen. Here we use differential expression, and correlation- and interaction-based network approaches to analyse the host response to infection with M. bovis at the transcriptome level to identify core infection response pathways and gene modules. These outputs were then integrated with genome-wide association study (GWAS) data sets to enhance detection of genomic variants for susceptibility/resistance to M. bovis infection.
Results
The host gene expression data consisted of RNA-seq data from bovine alveolar macrophages (bAM) infected with M. bovis at 24 and 48 h post-infection (hpi) compared to non-infected control bAM. These RNA-seq data were analysed using three distinct computational pipelines to produce six separate gene sets: 1) DE genes filtered using stringent fold-change and P-value thresholds (DEG-24: 378 genes, DEG-48: 390 genes); 2) genes obtained from expression correlation networks (CON-24: 460 genes, CON-48: 416 genes); and 3) genes obtained from differential expression networks (DEN-24: 339 genes, DEN-48: 495 genes). These six gene sets were integrated with three bTB breed GWAS data sets by employing a new genomics data integration tool—gwinteR. Using GWAS summary statistics, this methodology enabled detection of 36, 102 and 921 prioritised SNPs for Charolais, Limousin and Holstein-Friesian, respectively.
Conclusions
The results from the three parallel analyses showed that the three computational approaches could identify genes significantly enriched for SNPs associated with susceptibility/resistance to M. bovis infection. Results indicate distinct and significant overlap in SNP discovery, demonstrating that network-based integration of biologically relevant transcriptomics data can leverage substantial additional information from GWAS data sets. These analyses also demonstrated significant differences among breeds, with the Holstein-Friesian breed GWAS proving most useful for prioritising SNPS through data integration. Because the functional genomics data were generated using bAM from this population, this suggests that the genomic architecture of bTB resilience traits may be more breed-specific than previously assumed.
“…Using the M. marinum-zebrafish model, Cronan et al have found recently that granuloma Mjs undergo reprograming, which involves Ecadherin-dependent formation of fusogenic epithelial cell (44). In TB, ESAT6 plus TLR2 can activate iNOS/NO and ROS signaling to reduce the trimethylation of H3K27, thereby promoting the expression of EMMM that improved the transformation of Mjs into ECs (45).…”
Mycobacteriosis, mostly resulting from Mycobacterium tuberculosis (MTb), nontuberculous mycobacteria (NTM), and Mycobacterium leprae (M. leprae), is the long-standing granulomatous disease that ravages several organs including skin, lung, and peripheral nerves, and it has a spectrum of clinical-pathologic features based on the interaction of bacilli and host immune response. Histiocytes in infectious granulomas mainly consist of infected and uninfected macrophages (Mφs), multinucleated giant cells (MGCs), epithelioid cells (ECs), and foam cells (FCs), which are commonly discovered in lesions in patients with mycobacteriosis. Granuloma Mφ polarization or reprogramming is the crucial appearance of the host immune response to pathogen aggression, which gets a command of endocellular microbe persistence. Herein, we recapitulate the current gaps and challenges during Mφ polarization and the different subpopulations of mycobacteriosis.
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