Mus musculus
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ABSTRACT:
PROVIDER: PRJNA147155 | ENA |
REPOSITORIES: ENA
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Project description:Background: M.tuberculosis is one of the most prevalent and deadly human pathogens. The molecular mechanisms determining the outcomes of an infection with M.tuberculosis, that range from resistance to an active progressive disease, remain incompletely understood. Here we provide the evidence that IL-1alpha plays a critical and non-redundant role in enabling host resistance to pulmonary M.tuberculosis infection in mice that develop functional pathogen-specific adaptive immunity. Mechanistically, IL-1alpha-deficient mice fail to control M.tuberculosis replication in vivo at a level of individual infected cells and succumb to progressive disease at the late phase of infection. Furthermore, we show that IL-1alpha from hematopoietic compartment through IL-1RI operates upstream of TNFRI-signaling pathway and the lack of IL-1alpha leads to the continuous influx of monocytes that acquire a hyper-inflammatory phenotype and contribute to pathology, rather than to a pathogen control. Cell-type-specific restoration of IL-1alpha expression in CD11c+ subsets of lung leukocytes resulted in reduced levels of inflammatory marker expression on lung cells and improved survival IL-1alpha-deficient mice after M.tuberculosis infection. In humans, genetic analysis of single nucleotide polymorphisms in 14 genes implicated in IL-1-IL-1R signaling pathway revealed association of genetic variations in IL-1alpha and IL-1RAP genes with human susceptibility to pulmonary tuberculosis. Our results implicate IL-1alpha as a principal factor of host resistance to M.tuberculosis and IL-1alpha-driven cell-cell crosstalk as a key step in triggering M.tuberculosis control mechanisms that are critical for host survival.
2019-09-03 | GSE32619 | GEO
Project description:The cytokine IL-10 deactivates macrophages and has been shown to impair resistance to mycobacterial infection. We have infected transgenic mice overexpressing IL-10 under control of the macrophage-specific CD68 promoter (macIL-10tg mice) with Mycobacterium tuberculosis by aerosol and found increased bacterial loads in the lungs of macIL-10tg mice. To identify programs of genes regulated by IL-10 and associated with increased mycobacterial replication, genome-wide expression analysis was performed. Experiment Overall Design: Impact of IL-10 pulmonary gene expression in mouse M. tuberculosis infection
2009-01-17 | E-GEOD-14316 | biostudies-arrayexpress
Project description:Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis (TB) are incompletely understood. Here we show a role for eosinophils in host resistance to Mtb infection. In humans, eosinophils are found in resected human TB lung lesions and autopsy granulomas. Eosinophils are also found in granulomas in zebrafish, mice, and non-human primates, where they are functionally activated and degranulate. Transcriptional profiling of lung tissue after Mtb infection of mice, that selectively lack eosinophils, revealed changes in neuronal associated pathways. Importantly, employing several independent models of eosinophil deficiency in mice, we demonstrate that eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings establish an unexpected role for eosinophils, granulocytes typically associated with type II inflammation, in host resistance against Mtb, a major human bacterial pathogen.
2021-08-01 | GSE165871 | GEO
Project description:Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). we have used human monocyte and a mouse model of pulmonary TB to investigate whether treatment with PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection.
2013-06-28 | GSE48027 | GEO
Project description:Using cell-based approaches and experimental mouse models for pulmonary TB we unveiled MDSCs as new myeloid populations directly interacting with Mycobacterium tuberculosis (Mtb). MDSCs readily phagocytosed Mtb, released proinflammatory (IL-6, IL-1α) and immunomodulatory (IL-10) cytokines while retaining their suppressive capacity. MDSCs were identified at the site of infection in disease-resistant and -susceptible mice during pulmonary TB. Excessive MDSC accumulation in lungs correlated with elevated surface expression of IL-4Rα and heightened TB lethality.
2014-12-21 | GSE57124 | GEO
Project description:Host-pathogen interactions in Mycobacterium tuberculosis infection still remain poorly understood. We investigated the host immune response to different reference Mycobacterium tuberculosis strains in THP-1 cells. Major differences in the gene expression profiles were identified in response to infection with these strains. These findings shed new insights into the dynamic variation in tuberculosis immune response and pathogenesis. We used Affymetrix GeneChip Human Exon 1.0 ST microarrays to investigate host differential gene expression in response to different Mycobacterium tuberculosis strains.
2024-10-24 | GSE246736 | GEO
Project description:Using cell-based approaches and experimental mouse models for pulmonary TB we unveiled MDSCs as new myeloid populations directly interacting with Mycobacterium tuberculosis (Mtb). MDSCs readily phagocytosed Mtb, released proinflammatory (IL-6, IL-1M-NM-1) and immunomodulatory (IL-10) cytokines while retaining their suppressive capacity. MDSCs were identified at the site of infection in disease-resistant and -susceptible mice during pulmonary TB. Excessive MDSC accumulation in lungs correlated with elevated surface expression of IL-4RM-NM-1 and heightened TB lethality. Microarray experiments were performed as dual-color hybridizations on Agilent mouse whole genome catalog 44K arrays. To compensate for dye-specific effects, a dye-reversal color-swap was applied.
2014-12-21 | E-GEOD-57124 | biostudies-arrayexpress
Project description:Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). we have used human monocyte and a mouse model of pulmonary TB to investigate whether treatment with PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection. Mice were infected with Mtb and treatment with PZA was started at 28 days post-infection. At 42 days and 63 days post-infection, group of animals were euthanized and lung tissue was collected to isolate total RNA and used in microarray experiments. Mtb-infected, untreated animals served as controls.
2013-06-28 | E-GEOD-48027 | biostudies-arrayexpress
Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 1] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL?12, IL?1 and TNF??, as well as IFN?? and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL?10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease. Macrophages were derived from C57Bl/6 bone marrow, plated and infected with Mtb H37Rv (or not) in duplicate wells. Samples were then harvested for RNA at time 0 (uninfected only), 15m, 30m, 1hr, 3hr, 6hr and 24hr.
2013-09-05 | E-GEOD-47672 | biostudies-arrayexpress
Project description:Background. An exacerbated oxidative stress response can regulate cellular necrosis by triggering lipid peroxidation in an iron-dependent manner and this form of necrotic death has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. Here we examined the role of Bach1, a transcription factor that represses a major set of antioxidant genes, in regulating host resistance to Mtb. We found that BACH1 expression is associated with and predicts active pulmonary tuberculosis in humans. In response to Mtb infection in vitro and in vivo, ablation of Bach1 increased the levels of glutathione as well as enhanced the expression of Gpx4, an enzyme that regulates lipid peroxidation. Consistent with these observations, Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death and infected Bach1-deficient mice displayed a striking reduction in bacterial loads as well as pulmonary necrosis and lipid peroxidation accompanied by enhanced survival. In addition, single-cell RNAseq analysis of the lungs of Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with suppression of ferroptosis. Finally, deletion of Bach1 in B6.Sst1S mice, an inbred strain that exhibits the necrotic lung pathology similar to that seen in human TB, enhanced host resistance to Mtb while significantly reducing tissue necrosis. These findings identify Bach1 and its regulation of the oxidative stress response as an important modulator of cellular and tissue necrosis as well as host resistance in Mtb infection.
2023-09-07 | GSE236853 | GEO