Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Quantitative omics reveals that type I and II IFNs alter bacterial vacuole compositions to restrict infection in macrophages and lungs

ABSTRACT: The innate defense mechanisms that control infections with intracellular bacteria are still incompletely understood. Here we show that type I and II IFNs are key regulators of the early gene expression and the host-protective immune response during Legionella pneumophila-induced pneumonia. Using mixed bone marrow-chimeric mice and isolated cells we indicate that both IFNs protect against L. pneumophila by activating an alveolar macrophage-intrinsic antibacterial defense pathway. Quantitative mass spectrometry analysis reveals that both IFNs markedly alter the protein composition of purified Legionella-containing vacuoles, and integrated network analysis defines distinct subsets of IFN-regulated proteins. Subsequent experiments uncover Immunoresponsive gene 1 (Irg1) as a central effector that restricts the bacteria through production of itaconic acid. Collectively, we provide a comprehensive analysis of IFN-mediated effects on gene expression and the bacterial vacuole proteome, and show that L. pneumophila is restricted by an Irg1-dependent production of a bactericidal metabolite.

ORGANISM(S): Mus musculus

PROVIDER: GSE60085 | GEO | 2015/01/01

SECONDARY ACCESSION(S): PRJNA257451

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Quantitative omics reveals that type I and II IFNs alter bacterial vacuole compositions to restrict infection in macrophages and lungs

Project description:The innate defense mechanisms that control infections with intracellular bacteria are still incompletely understood. Here we show that type I and II IFNs are key regulators of the early gene expression and the host-protective immune response during Legionella pneumophila-induced pneumonia. Using mixed bone marrow-chimeric mice and isolated cells we indicate that both IFNs protect against L. pneumophila by activating an alveolar macrophage-intrinsic antibacterial defense pathway. Quantitative mass spectrometry analysis reveals that both IFNs markedly alter the protein composition of purified Legionella-containing vacuoles, and integrated network analysis defines distinct subsets of IFN-regulated proteins. Subsequent experiments uncover Immunoresponsive gene 1 (Irg1) as a central effector that restricts the bacteria through production of itaconic acid. Collectively, we provide a comprehensive analysis of IFN-mediated effects on gene expression and the bacterial vacuole proteome, and show that L. pneumophila is restricted by an Irg1-dependent production of a bactericidal metabolite. 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.

2015-01-01 | E-GEOD-60085 | biostudies-arrayexpress

Role of the transcriptional regulator SP140 in resistance to bacterial infection via repression of type I interferons

Project description:Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140–/– mice and find they are susceptible to infection by Legionella pneumophila and Mycobacterium tuberculosis. Susceptibility of Sp140–/– mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar–/–). Our results implicate Sp140 as an important repressor of type I IFNs that is essential for resistance to bacterial infections.

2021-02-04 | GSE166114 | GEO

Quorum sensing mediates the emergence of peripheral transmissive Legionella within the pathogen vacuole, selective escape and efficient spread

Project description:Legionella pneumophila, the causative agent of the severe pneumonia Legionnaires’ disease, replicates in free-living protozoa as well as in macrophages within a distinct compartment, the Legionella-containing vacuole (LCV). switches between a replicative, non-virulent and a motile, virulent phase. The timing, spatial organization, cues and functional consequences of the biphasic life cycle are not well understood. In this study, we show on a single cell level that bacterial clusters within a distinct pathogen vacuole develop spatially organized and functionally distinct subpopulations over time. At late stages of infection (>42 h), individual motile (PflaA-GFP-positive) and virulent (PralF-GFP-positive) L. pneumophila emerged at the periphery of clusters comprising non-growing bacteria. Comparative proteomics of PflaA-GFP-positive and PflaA-GFP-negative L. pneumophila subpopulations revealed distinct proteomes with flagellar proteins or cell division proteins being exclusively produced by the former or the latter, respectively. Towards the end of an infection cycle (~48 h), PflaA-GFP-positive L. pneumophila preferentially escaped the LCV and the bursting host cell, and the motile subpopulation promoted spreading of L. pneumophila. The emergence of peripheral motile L. pneumophila, LCV escape, host cell lysis and spreading of the bacteria to the environment is controlled by the Lqs quorum sensing system. Thus, quorum sensing controls the emergence of a subpopulation of transmissive L. pneumophila at the LCV periphery, and phenotypic heterogeneity underlies the intracellular bi-phasic life cycle of L. pneumophila.

2021-08-09 | PXD023787 | Pride

The Legionella-driven PtdIns(4)P gradient at LCV-ER membrane contact sites promotes Vap-, OSBP and Sac1-dependent pathogen vacuole remodeling

Project description:The causative agent of Legionnaires’ disease, Legionella pneumophila, governs interactions with host cells by secreting ca. 330 different “effector” proteins. The facultative intracellular bacteria replicate in macrophages and amoeba within a unique compartment, the Legionella-containing vacuole (LCV). Hallmarks of LCV formation are the phosphoinositide (PI) lipid conversion from PtdIns(3)P to PtdIns(4)P, fusion with endoplasmic reticulum (ER)-derived vesicles and a tight association with the ER. Proteomics of purified LCVs revealed the presence of membrane contact sites (MCS) proteins implicated in lipid exchange. Using dually fluorescence-labeled Dictyostelium discoideum amoeba, we reveal that the VAMP-associated protein (Vap), the PtdIns(4)P 4-phosphatase Sac1, and the large fusion GTPase Sey1/atlastin-3 localize to the ER, but not to the LCV membrane, and these ER-resident proteins promote intracellular replication of L. pneumophila and LCV remodeling. Moreover, oxysterol binding proteins (OSBPs) exclusively localize to the ER (OsbH) or the LCV membrane (OsbK), respectively, and promote (OsbH) or restrict (OsbK) intracellular replication of L. pneumophila and LCV expansion. Furthermore, the PtdIns(4)P-subverting L. pneumophila effectors LepB and SidC also promote LCV remodeling. Taken together, the Legionella-driven PtdIns(4)P gradient at LCV-ER MCSs promotes Vap-, OSBP- and Sac1-dependent pathogen vacuole remodeling.

2023-02-21 | PXD034490 | Pride

LPS stimulation of human PBMC-derived macrophages

Project description:Immunoresponsive gene 1 (IRG1) is one of the highest induced genes in macrophages under pro-inflammatory conditions and its function has been recently described: it codes for immune-responsive gene 1 protein/cis-aconitic acid decarboxylase (IRG1/CAD), an enzyme catalyzing the production of itaconic acid from cis-aconitic acid, a tricarboxylic acid (TCA) cycle intermediate. Itaconic acid possesses specific antimicrobial properties inhibiting isocitrate lyase, the first enzyme of the glyoxylate shunt, an anaplerotic pathway that bypasses the TCA cycle and enables bacteria to survive on limited carbon conditions. To elucidate the mechanisms underlying itaconic acid production through IRG1 induction in macrophages, we examined the transcriptional regulation of IRG1. Using a combination of literature information, transcription factor prediction models and genome-wide expression arrays, we inferred the regulatory network of IRG1 in mouse and human macrophages. 3 unstimulated (Control) and 3 LPS-stimulated human PBMC-derived macrophages

2016-02-25 | E-GEOD-76561 | biostudies-arrayexpress

LPS stimulation of Mouse (RAW 264.7) macrophages

2016-02-25 | E-GEOD-76562 | biostudies-arrayexpress

Type II interferon-dependent antibacterial defense in the lungs is compromised in diabetes

Project description:Diabetes mellitus is associated with an increased risk of pneumonia, which is often caused by so-called typical and atypical pathogens including Streptoccocus pneumoniae and Legionella pneumophila, respectively. Here, we employed a varity of mouse models to investigate how diabetes influences pulmonary antibacterial immunity. Following intranasal infection with Streptoccocus pneumoniae or Legionella pneumphila, type 2 diabetic and prediabetic mice had higher bacterial loads in their lungs as compared to control animals. Single cell RNA sequencing, flow cytometry, and functional analyses revealed a compromised type II IFN (IFNg) production by natural killer cells in diabetic and prediabetic mice, which was linked to reduced IL-12 production by CD103+ dendritic cells. Treatment with IFNg rescued antibacterial defense against L. pneumophila but not against S. pneumoniae in diabetic animals, although impaired production of IFNg also contributed to the compromised anti-pneumococcal resistance in diabetic mice. These findings uncover a mechanism that could help to explain why type 2 diabetes predisposes to pneumonia. We establish proof of concept for host-directed treatment strategies to reinforce compromised IFNg-mediated antibacterial defense against atypical lung pathogens.

2024-11-19 | GSE270694 | GEO

LPS stimulation of Mouse (RAW 264.7) macrophages

2016-02-25 | GSE76562 | GEO

LPS stimulation of human PBMC-derived macrophages

2016-02-25 | GSE76561 | GEO

Influence of two bacterial effectors on the transcriptional landscape of the host cell

Project description:To investigate the role of two secreted bacterial proteins (LphD and RomA) of Legionella pneumophila we infected THP-1 monocytes with GFP-producing bacteria. After 7 hours of infection, the cells were sorted (to enrich infected cells based on GFP-signal) and RNAseq was performed on the infected and sorted cells.

2023-04-05 | GSE207487 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data