Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA112061 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Granulomas function in humans during tuberculosis by focusing production of host antimicrobial factors against the causative bacterial agent Mycobacterium tuberculosis to contain infection. We show that mice unable to produce nitric oxide –itself an important antimicrobial molecule- demonstrate functional granulomas in the lung able to control infection after dermal infection. Disease in the lung was activated by administration of neutralising antibody against either TNF-α, which disrupted granuloma integrity, or INF-γ, which resulted in development of caseous necrosis within granulomas reminiscent of active human tuberculosis. In the latter case, the serpin protease inhibitor serpinb3a and its target protease, cathepsin G are highly expressed in cells local to necrotic regions in granulomas and serpinb3a induces necrosis of infected macrophages independently of cathepsin G binding. Therefore a single host protein is capable of inducing necrosis and bacterial growth during intracellular infection.
2010-12-22 | GSE14826 | GEO
Project description:Necrotic cell death represents a major pathogenic mechanism of Mycobacterium tuberculosis (Mtb) infection. It is increasingly evident that Mtb induces several types of regulated necrosis but how these are interconnected and linked to the release of pro-inflammatory cytokines remains unknown. Exploiting a clinical cohort of tuberculosis patients, we show here that the number and size of necrotic lesions correlates with IL-1β plasma levels as a strong indicator of inflammasome activation. Our mechanistic studies reveal that Mtb triggers mitochondrial permeability transition (mPT) and subsequently extensive macrophage necrosis which requires activation of the NLRP3 inflammasome. NLRP3 driven mitochondrial damage is dependent on proteolytic activation of the pore forming effector protein gasdermin D (GSDMD) which links two distinct cell death machineries. Intriguingly, GSDMD, but not the membranolytic mycobacterial ESX-1 secretion system is dispensable for IL-1β secretion from Mtb-infected macrophages. Thus, our study dissects a novel mechanism of pathogen induced regulated necrosis by identifying mitochondria as central regulatory hubs capable of delineating cytokine secretion and lytic cell death.
2022-02-17 | PXD029017 | Pride
Project description:An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis.
2007-09-29 | E-SMDB-4062 | biostudies-arrayexpress
Project description:An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis. The quality controls were biological replicate and technical replicate
2007-08-21 | E-GEOD-8839 | biostudies-arrayexpress
Project description:Mycobacterium infection gives rise to granulomas predominantly composed of inflammatory M1-like macrophages, with bacteria-permissive M2 macrophages also detected in deep granulomas. Our histological analysis of Mycobacterium bovis bacillus Calmette-Guerin-elicited granulomas in guinea pigs revealed that S100A9-expressing neutrophils bordered a unique M2 niche within the inner circle of concentrically multilayered granulomas. We evaluated the effect of S100A9 on macrophage M2 polarization based on guinea pig studies. S100A9-deficient mouse neutrophils abrogated M2 polarization, which was critically dependent on COX-2 signaling in neutrophils. Mechanistic evidence suggested that nuclear S100A9 interacts with C/EBPβ, which cooperatively activates the Cox-2 promoter and amplifies prostaglandin E2 production, followed by M2 polarization in proximal macrophages. Since the M2 populations in guinea pig granulomas were abolished via treatment with celecoxib, a selective COX-2 inhibitor, we propose the S100A9/Cox-2 axis as a major pathway driving M2 niche formation in granulomas.
2023-03-01 | GSE162991 | GEO
Project description:An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis.
2007-08-22 | GSE8839 | GEO
Project description:UMR106-01 osteoblastic cells are a model for studying bone mineralization. We have shown that mineralization is temporally synchronized within cultures grown under defined conditions . Cells are plated at time zero and differentiate into osteoblastic phenotype by 64 h later. If an exogenous phosphate source is added to the cultures, the cells form and deposit hydroxyapatite mineral within distinct extracellular supramolecular lipid protein complexes termed biomineralization foci (BMF) starting 12 h later. Mineralization is largely complete by 24 h later (88 h after plating). We have also shown that AEBSF, covalent serine protease inhibitor, blocks mineralization within BMF and inhibits the fragmentation of several proteins related to biomineralization. The present experiment was designed to test whether AEBSF treatment for 12 h has an effect on transcription by UMR106-01 osteoblastic cells. AEBSF is known to inactivate several serine proteases including SKI-1 (site 1, subtilisin kexin protease-1).SKI-1 functions intracellularly to activate transmembrane bound transcription factor precursors releasing the transcriptionally active N-terminal portions to imported into the nucleus. Thus, if AEBSF blocks transcription of mineralization related genes, it would support a role for SKI-1 in gene regulation in mineralizing UMR106-01 osteoblastic cells. Comparison of triplicate cultures treated with mineralizing conditions with triplicate cultures treated with AEBSF protease inhibitor for 12 h.
2010-11-13 | E-GEOD-21476 | biostudies-arrayexpress
Project description:To investigate the activation and polarisation of BMDMs during the course of pancreatitis, BMDMs were co-incubated with CCK-stimulated acinar cells (+/- the serine protease inhibitor nafamostat) for 6h in an in vitro experiment. The LPS treatment served as a positive control.
2022-03-01 | GSE192517 | GEO
Project description:Alpha-1-antitrypsin (AAT), a serine protease inhibitor produced mainly by the liver, is the third most abundant protein in plasma. Individuals who possess homozygous Z-AAT genotype have severe AAT deficiency and are at risk for early-onset emphysema, bronchiectasis, cirrhosis, panniculitis, and vasculitis. While a canonical receptor for AAT has not been identified, AAT can be internalized into the cytoplasm and is known to affect gene regulation. Since AAT has significant anti-inflammatory properties affecting many cell types including macrophages, we examined whether AAT binds the cytoplasmic glucocorticoid receptor (GR) in macrophages. We report the novel finding that AAT binds to GR in macrophages using several approaches, including co-immunoprecipitation, mass spectrometry, microscale thermophoresis, and in silico molecular modeling. We further demonstrate that AAT induction of angiopoietin-like 4 protein and AAT inhibition of lipopolysaccharide-induced nuclear factor-kappa B activation and interleukin-8 production are mediated, in part, through AAT–GR interaction. Furthermore, this interaction contributes to a host-protective role against Mycobacterium tuberculosis in macrophages. The interaction of AAT and GR described in this study identifies a mechanism for the anti-inflammatory and host-protective properties of AAT.
2022-08-24 | PXD030989 | Pride
Project description:Most individuals infected with Mycobacterium tuberculosis can control the infection by forming and maintaining TB granulomas at the local infection foci. However, when the chronic infection (also known as latency) becomes active, the caseous center of TB granuloma enlarges, and it liquefies and cavitates, ultimately releasing bacilli into airway. Deciphering how genes are regulated within TB granulomas will help to understand the granuloma biology. Therefore, we performed genome-wide microarray on caseous human pulmonary TB granulomas and compared with normal lung tissues.
2010-06-02 | GSE20050 | GEO