Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single cell analysis of diverse pathogen responses defines a molecular roadmap for generating antigen-specific immunity

ABSTRACT: The immune system generates pathogen-tailored responses. The precise innate immune cell types and pathways that direct robust adaptive immune responses have not been fully characterized. By using fluorescent pathogens combined with massively parallel single cell RNA-seq, we comprehensively characterized the initial 48 hours of the innate immune response to diverse pathogens. We found that across all pathogens tested, most of the lymph node cell types and states showed little pathogen-specificity. In contrast, the rare antigen-positive cells displayed pathogen-specific transcriptional programs as early as 24 hours after immunization. In addition, mycobacteria activated a specific NK driven IFNγ response. Depletion of NK cells and IFNγ showed that IFNγ initiated a monocyte specific signaling cascade, leading to production of major chemokines and cytokines that promote Th1 development. Our systems immunology approach sheds light on early events in innate immune responses and may help further development of safe and efficient vaccines.

ORGANISM(S): Mus musculus

PROVIDER: GSE125044 | GEO | 2019/02/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

PIM1 controls GBP1 activity to limit self-damage and guard against pathogen infection

Project description:Pathogen virulence factors interfere with various cellular activities, a disruption that can trigger innate immune responses. Interferon-gamma (IFNγ)-inducible antimicrobial factors, such as the guanylate binding proteins (GBPs), promote cell-intrinsic defense against intracellular pathogens by directly attacking intracellular pathogens and by committing the infected host cell to programmed cell death. GBPs are large GTPases that traffic to pathogens in the cytosol or that reside within membrane-bound compartments and restrict microbial growth. We discovered that ectopic expression of the prototypical IFNγ-inducible GTPase, Guanylate Binding Protein 1 (GBP1), in the absence of IFNγ kills human macrophages, accompanied by fragmentation of the Golgi apparatus. Exposure to IFNγ improved host cell survival via the activity of PIM1 kinase. PIM1 phosphorylates GBP1 and imposes its sequestration by 14-3-3σ to prevent membrane association of GBP1. Analysis by cryo-EM showed that a 14-3-3σ-dimer trapped GBP1 in an inactive monomeric state. This control mechanism becomes evident during Toxoplasma gondii infection, where the effector protein TgIST interferes with IFNγ-signaling and thereby unintentionally depletes the short-lived kinase PIM1. This, in turn, increases GBP1-driven control of the pathogen. Uninfected bystander cells are spared during inflammation, while the infected cells restrain the pathogen in a rapid GBP1-dependent manner. Our work establishes PIM1 as a bait for pathogen virulence factors, thus safeguarding the integrity of IFNγ-signaling. This work presents a new paradigm of IFNγ-dependent protection of uninfected cells against self-inflicted innate immune damage.

2023-07-26 | PXD029463 | Pride

Hobit confers tissue dependent programs to type 1 innate lymphoid cells

Project description:Innate responses against viral infection and other intracellular pathogens rely on immune cells that are capable of lysing infected cells and producing interferon-gamma (IFNγ). These cells encompass two major cell lineages: natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s). While NK cells have been extensively characterized, identification of ILC1s and their distinction from NK cells is less clear. The transcription factor Hobit encoded by Zfp683 has been put forth as a prototypic feature of ILC1s. By analyzing Zfp683 reporter, fate-map and deficient mice, we demonstrate that the impact of Hobit on ILC1 identity, transcriptional and functional programs is tissue- and context-dependent. Thus, ILC1s functionally adapt to local stimuli and tailor their responses to the tissue niche.

2021-12-06 | GSE185346 | GEO

Expression arrays of inflammatory Ly6C+ monocytes in mice primary or secondary challenged with Listeria monocytogenes

Project description:In this study we investigated the mechanisms involved in memory T-cell mediated protection using mice vaccinated with the intracellular bacterium Listeria monocytogenes. Our working hypothesis was that rapid activation of cells of the innate immune system, in particular inflammatory Ly6C+ monocytes, were essential in effective protection, in a memory T cell-dependent manner. Thus we generated a comprehensive comparison of the genetic program of activated Ly6C+ monocytes during a primary or a secondary infection with Listeria monocytogenes, at 8 hours post challenge infection. Abstract of corresponding publication: Cells of the innate immune system are essential for host defenses against primary microbial pathogen infections, yet their involvement in effective memory responses of vaccinated individuals has been poorly investigated. Here we show that memory T cells instruct innate cells to become potent effector cells in a systemic and a mucosal model of infection. Memory T cells controlled phagocyte, dendritic cell and NK or NK T cell mobilization and induction of a strong program of differentiation, which included their expression of effector cytokines and microbicidal pathways, all of which were delayed in non-vaccinated hosts. Disruption of IFN-gamma-signaling in Ly6C+ monocytes, dendritic cells and macrophages impaired these processes and the control of pathogen growth. These results reveal how memory T cells, through rapid secretion of IFN-gamma, orchestrate extensive modifications of host innate immune responses that are essential for effective protection of vaccinated hosts. Overall design: Inflammatory monocytes were purified (see below for isolation method) from 4 groups of 3 individual mice each (triplicate): (i) uninfected mice, (ii) primary infected, (iii) secondary infected, (iv) secondary infected and T-cell depleted 1 day before. Isolation of cells was done on 3 different days for true biological replicates.

2015-06-04 | E-GEOD-58014 | biostudies-arrayexpress

Single-cell transcriptomics reveal hyperacute cytokine and immune checkpoint axis in patients with poor neurological outcomes after cardiac arrest [BRI]

Project description:Neurological injury is a major driver for mortality among patients hospitalized after cardiac arrest (CA). The early systemic inflammatory response after CA is associated with neurological injury and mortality but remains poorly defined. We determine the innate immune network induced by clinical CA at single-cell resolution. Immune cell states diverge as early as 6h post-arrest between patients with good or poor neurological outcomes at hospital discharge. Nectin-2+ monocytes and Tim-3+ natural killer (NK) cell subpopulations associate with poor outcomes, and interactome analysis highlight their cross-talk via cytokines and immune checkpoints. Ex vivo studies on peripheral blood cells from CA patients demonstrate that immune checkpoints are a compensatory mechanism for the resolution of inflammation after CA. IFNγ/IL-10 induce Nectin-2 on monocytes; in a negative feedback loop, Nectin-2 suppresses IFNγ production by NK cells. The initial hours after CA may represent a window for therapeutic intervention in the resolution of inflammation via immune checkpoints.

2023-06-01 | GSE200118 | GEO

Single-cell transcriptomics reveal a hyperacute cytokine and immune checkpoint axis after cardiac arrest in patients with poor neurological outcome

2023-06-01 | GSE200117 | GEO

Tollip isoforms as key regulators of macrophage phenotype and response to LPS

Project description:Pathogen recognition via the Toll-like receptor (TLR) signaling pathways leads to inflammatory responses by innate immune cells. The Toll-interacting protein (Tollip) is an ubiquitin-binding protein which negatively regulates TLR signaling. We have previously described extensive alternative splicing of Tollip in human and mouse macrophages. In the current study we examined the role of two mouse Tollip isoforms in innate immune responses: the canonical full-length form (Tollip.a), and a novel 220 amino acid isoform (Tollip.b), which lacks the Ub-binding domain. We hypothesized that alternative splicing of this negative regulator contributes to the diversification of macrophage responses to pathogens. The function of the two Tollip isoforms was studied by over-expressing the variants in the macrophage-like cell line, RAW264.7.

2010-09-18 | E-TABM-795 | biostudies-arrayexpress

Genome-wide expression study of the responses of murine NK cells and dendritic cell subsets after poly(I:C) injection

Project description:The injection of the pathogen-associated molecular pattern Polyinosinic-polycytidylic acid (poly(I:C)) leads to the activation of various immune cells, including dendritic cells (DCs) and Natural Killer (NK) cells. This activation is due to different innate cytokines produced early after injection, in particular IFN-I. The objective of the study was to compare the pattern of expression of IFN-I stimulated genes between DC and NK cells. The project focused on a specific subset of conventional DC, CD8a DC, which responsiveness to IFN-I determines the capacity to activate CD8 T cells by cross-presentation of exogenous antigens. To identify the responses to IFN-I selectively induced in CD8a+ DC, we compared their gene expression profile to that of NK cells, using gene chips, before and after poly(I:C) stimulation. This study includes data from CD8a+ cDCs and NK cells purified by flow cytometry from the spleen of WT C57BL/6 mice, under steady-state conditions or 3 hours after administration of 100 ug poly(I:C) by intravenous injection. Two independent replicates were made for each cell type.

2012-10-17 | E-GEOD-39556 | biostudies-arrayexpress

Global analysis of gene expression reveals mRNA superinduction is required for the inducible immune response to a bacterial pathogen

Project description:The inducible innate immune response to infection requires a concerted process of gene expression that is regulated at multiple levels. Most global analyses of the innate immune response have focused on transcription induced by defined immunostimulatory ligands, such as lipopolysaccharide. However, the response to pathogens involves additional complexity, as pathogens interfere with virtually every step of gene expression. How cells respond to pathogen-mediated disruption of gene expression to nevertheless initiate protective responses remains unclear. We previously discovered that a pathogen-mediated blockade of host protein synthesis provokes the production of specific pro-inflammatory cytokines. It remains unclear how these cytokines are produced despite the global pathogen-induced block of translation. We addressed this question by using parallel RNAseq and ribosome profiling to characterize the response of macrophages to infection with the intracellular bacterial pathogen Legionella pneumophila. Our results reveal that mRNA superinduction is required for the inducible immune response to a bacterial pathogen.

2017-03-28 | GSE89184 | GEO

Expression arrays of inflammatory Ly6C+ monocytes in mice primary or secondary challenged with Listeria monocytogenes

2015-06-04 | GSE58014 | GEO

Chromatin accessibility analysis of wild type bone marrow-derived macrophages in response to Anisomycin, type II interferon and the combination of them or with p38 MAPK inhibitor PH-797804 (ATAC-Seq IFNg)

Project description:The innate immune system acts as the first line of defense against invasion of microbial pathogens. Here, macrophages play a substantial role in recognition, phagocytosis and killing of pathogens and the regulation of the innate immune response. Here, interferons play a crucial role in augmenting the antimicrobial functions of macrophages and their ability to produce mediators of immunoregulation. Pathogen recognition activates many different signaling pathways that interact to produce an innate response commensurate with the microbial challenge. The co-occurrence of signaling by sensors of stress and IFN receptors is a hallmark of innate responses to many viral and bacterial pathogens. Our results show changes in chromatin accessibility upon Anisomycin, a drug that induces stress-activation of MAPK pathways, IFNg stimulation and the combination of both or with p38 inhibitor PH-797804, Anisomycin and IFNg.

2022-12-18 | GSE199126 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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