Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cytotoxicity and secretion of gamma interferon are carried out by distinct CD8 T cells during Mycobacterium tuberculosis infection.

ABSTRACT: The host immune response is generally sufficient to contain Mycobacterium tuberculosis infection. It does not, however, efficiently prevent subsequent infection with M. tuberculosis or provide sterilizing immunity. While the understanding of the immune response generated against this pathogen is incomplete, improvements have been achieved due to advances in immunological tools. In this study, we analyzed the multifunctional nature of primary and memory CD8 T-cell responses generated during murine M. tuberculosis infection. We generated a recombinant M. tuberculosis strain expressing ovalbumin (OVA) epitopes in order to expand the peptides for the detection of CD8 T cells during M. tuberculosis infection and enable us to use OVA-specific reagents. Our results indicate that the majority of M. tuberculosis-specific CD8 T cells are limited to either cytotoxicity or the secretion of gamma interferon (IFN-gamma), with cytotoxicity being far more prevalent than IFN-gamma secretion. Memory CD8 T cells responded earlier and reached higher levels in the lungs than naïve CD8 T cells, as was expected. They were, however, less cytotoxic and secreted less IFN-gamma than newly primed CD8 T cells, suggesting that one factor contributing to bacterial persistence and lack of sterilizing immunity may be the low quality of memory cells that are generated.

SUBMITTER: Einarsdottir T

PROVIDER: S-EPMC2747936 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Gamma interferon release assays for detection of Mycobacterium tuberculosis infection.

Project description:Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

| S-EPMC3910908 | biostudies-other

Mycobacterium tuberculosis senses host Interferon-γ via the membrane protein MmpL10.

Project description:Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens. Several cytokines are known to increase virulence of bacterial pathogens, leading us to investigate whether Interferon-γ (IFN-γ), a central regulator of the immune defense against Mtb, has a direct effect on the bacteria. We found that recombinant and T-cell derived IFN-γ rapidly induced a dose-dependent increase in the oxygen consumption rate (OCR) of Mtb, consistent with increased bacterial respiration. This was not observed in attenuated Bacillus Calmette-Guérin (BCG), and did not occur for other cytokines tested, including TNF-α. IFN-γ binds to the cell surface of intact Mtb, but not BCG. Mass spectrometry identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner of IFN-γ, supported by molecular modelling studies. IFN-γ binding and the OCR response was absent in Mtb Δmmpl10 strain and restored by complementation with wildtype mmpl10. RNA-sequencing and RT-PCR of Mtb exposed to IFN-γ revealed a distinct transcriptional profile, including genes involved in virulence. In a 3D granuloma model, IFN-γ promoted Mtb growth, which was lost in the Mtb Δmmpl10 strain and restored by complementation, supporting the involvement of MmpL10 in the response to IFN-γ. Finally, IFN-γ addition resulted in sterilization of Mtb cultures treated with isoniazid, indicating clearance of phenotypically resistant bacteria that persist in the presence of drug alone. Together our data are the first description of a mechanism allowing Mtb to respond to host immune activation that may be important in the immunopathogenesis of TB and have use in novel eradication strategies.

| S-EPMC9715692 | biostudies-literature

Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis.

Project description:Immunity to Mycobacterium tuberculosis in humans and in mice requires interferon gamma (IFN-gamma). Whereas IFN-gamma has been studied extensively for its effects on macrophages in tuberculosis, we determined that protective immunity to tuberculosis also requires IFN-gamma-responsive nonhematopoietic cells. Bone marrow chimeric mice with IFN-gamma-unresponsive lung epithelial and endothelial cells exhibited earlier mortality and higher bacterial burdens than control mice, underexpressed indoleamine-2,3-dioxygenase (Ido1) in lung endothelium and epithelium, and overexpressed interleukin-17 (IL-17) with massive neutrophilic inflammation in the lungs. We also found that the products of IDO catabolism of tryptophan selectively inhibit IL-17 production by Th17 cells, by inhibiting the action of IL-23. These results reveal a previously unsuspected role for IFN-gamma responsiveness in nonhematopoietic cells in regulation of immunity to M. tuberculosis and illustrate the role of IDO in the inhibition of Th17 cell responses.

| S-EPMC2807991 | biostudies-literature

Mycobacterium tuberculosis exploits human interferon γ to stimulate macrophage extracellular trap formation and necrosis.

Project description:Human neutrophils form extracellular traps during M. tuberculosis infection, but a similar phenomenon has not been reported in human macrophages. Here we demonstrate that M. tuberculosis induces release of extracellular traps from human macrophages. This process is regulated by elastase activity, previously shown to regulate formation of extracellular traps by neutrophils. Interestingly, formation of extracellular traps by macrophages during M. tuberculosis infection is inducible by interferon γ (IFN-γ). These traps are mainly produced by heavily infected macrophages. Accordingly, IFN-γ is found to stimulate M. tuberculosis aggregation in macrophages. Both IFN-γ-inducible events, extracellular trap formation and mycobacterial aggregation, require the ESX-1 secretion system. In addition, IFN-γ is found to enhance ESX-1-mediated macrophage necrosis. In the absence of ESX-1, IFN-γ does not restore any extracellular trap formation, mycobacterial aggregation, or macrophage necrosis. Thus, initial characterization of macrophage extracellular trap formation due to M. tuberculosis infection led to the uncovering of a novel role for IFN-γ in amplifying multiple effects of the mycobacterial ESX-1.

| S-EPMC3666134 | biostudies-literature

Modulation of gamma interferon receptor 1 by Mycobacterium tuberculosis: a potential immune response evasive mechanism.

Project description:Mycobacterium tuberculosis inhibits gamma interferon (IFN-gamma)-mediated antimycobacterial action by adopting diverse mechanisms. IFN-gamma binds to its receptor, IFN-gammaR, in order to initiate proper signaling. We have observed reduced surface expression levels of IFN-gamma receptor 1 (IFN-gammaR1) in untreated pulmonary tuberculosis patients compared to those in healthy individuals (P < 0.01). Following antitubercular therapy, the expression of IFN-gammaR1 was restored in these patients. To delineate the mechanism by which M. tuberculosis modulates IFN-gammaR1, in vitro experiments were designed, wherein the down modulation of IFN-gammaR1 surface expression was observed for CD14+ cells in peripheral blood mononuclear cells (PBMCs) cocultured with live M. tuberculosis compared to that for uninfected cells (P < 0.01). No modulation of IFN-gammaR1 expression was observed for CD14+ cells in PBMCs infected with Mycobacterium smegmatis. A time-dependent decrease in IFN-gammaR1 mRNA expression was observed for PBMCs infected with M. tuberculosis. Similar down modulation of IFN-gammaR1 protein and mRNA expression in phorbol myristate acetate-differentiated THP-1 cells (pdTHP-1) by M. tuberculosis was observed (P < 0.01). Using reporter gene analysis of 5' deletion constructs of the IFN-gammaR1 gene (IFNGR1) promoter, the decrease in IFN-gammaR1 mRNA in M. tuberculosis-infected pdTHP-1 cells was shown to be due to the decreased transcription of IFNGR1. By immunoblotting and electrophoretic mobility shift assays, the down regulation of stimulating protein 1 (Sp1) expression and its recruitment on the phorbol ester-responsive element of the IFNGR1 promoter in M. tuberculosis-infected pdTHP-1 cells was observed. This down regulation of Sp1 in pdTHP-1 cells cocultured with M. tuberculosis may be responsible for the down regulation of IFN-gammaR1 expression, thereby potentially altering its receptivity to IFN-gamma.

| S-EPMC1865798 | biostudies-literature

Boosting effect of IL-7 in interferon gamma release assays to diagnose Mycobacterium tuberculosis infection.

Project description:BackgroundA quarter of the world's population is estimated to be infected with Myobacterium tuberculosis (Mtb). Infection is detected by immune response to M. tuberculosis antigens using either tuberculin skin test (TST) and interferon gamma release (IGRA's), tests which have low sensitivity in immunocompromised. IL-7 is an important cytokine for T-cell function with potential to augment cytokine release in in-vitro assays. This study aimed to determine whether the addition of IL-7 in interferon-gamma release assays (IGRAs) improves its diagnostic performance of Mtb infection.Methods44 cases with confirmed TB and 45 household contacts without TB were recruited and 1ml of blood was stimulated in two separate IGRA's tube set: one set of standard Quantiferon TB gold tubes mitogen, TB antigen and TB Nil; one set of customized Quantiferon TB gold tubes with added IL-7. Following IFN-γ and IP-10 release was determined using ELISA.ResultsWe found that the addition of IL-7 led to significantly higher release of IFN-γ in individuals with active TB from 4.2IU/ml (IQR 1.4-6.9IU/ml) to 5.1IU/ml (IQR 1.5-8.1IU/ml, p = 0.0057), and we found an indication of a lower release of both IFN-γ and IP-10 in participants with negative tests.ConclusionsIn TB cases addition of IL-7 in IGRA tubes augments IFN-γ but not IP-10 release, and seems to lower the response in controls. Whether IL-7 boosted IGRA holds potential over standard IGRA needs to be confirmed in larger studies in high and low TB incidence countries.

| S-EPMC6114790 | biostudies-literature

Adults with Mycobacterium tuberculosis infection and pre-diabetes have increased levels of QuantiFERON interferon-gamma responses.

Project description:BackgroundDiabetes is associated with increased prevalence of TB infection in the US. We assessed associations between diabetes and interferon-gamma (IFN-γ) TB antigen response among adults with TB infection using US representative data.MethodsNational Health and Nutrition Examination (NHANES) participants >19 years from 2011 to 2012 with positive QuantiFERON®-TB Gold-In-Tube (QFT) results were eligible. Diabetes was defined by combination of self-report and glycated hemoglobin (HbA1c). Quantitative IFN-γ TB antigen was classified as high (≥10 IU/mL), intermediate (1.01-9.99 IU/mL), or low (0.35-1.00 IU/mL). Analyses accounted for NHANES weighted design.ResultsAmong NHANES participants >19 years, n = 513 had positive QFT (5.9%). Among those with positive QFT, diabetes prevalence was 22.2% and pre-diabetes was 25.9%. Overall, 16.7% of positive QFT participants had high IFN-γ TB antigen levels including 21.7% among those with diabetes, 20.8% among those with pre-diabetes, and 12.6% among euglycemic participants. In adjusted analyses, high IFN-γ TB antigen response was more common among those with pre-diabetes (aOR 1.9, 95%CI 1.0, 3.6) compared to euglycemic participants.ConclusionHigher antigen responses may reflect immunopathy consistent with an exaggerated inflammatory but ineffectual response to TB or a reflection of more Mtb replication in participants with pre-diabetes or diabetes.

| S-EPMC7275930 | biostudies-literature

Phosphorylation of mitogen-activated protein kinases contributes to interferon γ production in response to Mycobacterium tuberculosis.

Project description:Immune control of Mycobacterium tuberculosis depends on interferon γ (IFN-γ)-producing CD4(+) lymphocytes. Previous studies have shown that T cells from patients with tuberculosis produce less IFN-γ, compared with healthy donors, in response to mycobacterial antigens, although IFN-γ responses to mitogens are preserved. In this work, we found that M. tuberculosis-induced IFN-γ production by human T cells correlated with phosphorylation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38. Moreover, the majority of IFN-γ-producing T cells expressed signaling lymphocyte activation molecule (SLAM), and SLAM activation further increased ERK phosphorylation. Interestingly, patients with tuberculosis had delayed activation of ERK and p38, and this was most marked in patients with the poorest IFN-γ responses (ie, low responders). Besides, SLAM signaling failed to phosphorylate ERK in low responders. Our findings suggest that activation of p38 and ERK, in part through SLAM, mediates T-cell IFN-γ production in response to M. tuberculosis, a pathway that is defective in patients with tuberculosis.

| S-EPMC3532830 | biostudies-literature

Interferon-γ-responsive non-hematopoietic cells regulate the immune response to Mycobacterium tuberculosis

Project description:Immunity to Mycobacterium tuberculosis in humans and in mice requires interferon gamma (IFNγ). Wheras IFNγ has been studied extensively for its effects on macrophages in tuberculosis, we determined that protective immunity to tuberculosis also requires IFNγ-responsive non-hematopoietic cells. Bone marrow chimeric mice with IFNγ-unresponsive lung epithelial and endothelial cells exhibited earlier mortality and higher bacterial burdens than control mice, under-expressed indoleamine-2,3-dioxygenase (Ido1) in lung endothelium and epithelium and over-expressed interleukin-17 (IL-17) with massive neutrophilic inflammation in the lungs. We also found that the products of IDO catabolism of tryptophan selectively inhibit IL-17 production by Th17 cells, by inhibiting the action of IL-23. These results reveal a previously-unsuspected role for IFNγ responsiveness in non-hematopoietic cells in regulation of immunity to M. tuberculosis, and reveal a mechanism for IDO inhibition of Th17 cell responses.

2009-11-25 | GSE19148 | GEO

Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-gamma (IFN-gamma)-dependent manner.

Project description:Protection against infection with Mycobacterium tuberculosis demands IFN-γ. SOCS1 has been shown to inhibit responses to IFN-γ and might thereby play a central role in the outcome of infection. We found that M. tuberculosis is a highly efficient stimulator of SOCS1 expression in murine and human macrophages and in tissues from infected mice. Surprisingly, SOCS1 reduced responses to IL-12, resulting in an impaired IFN-γ secretion by macrophages that in turn accounted for a deteriorated intracellular mycobacterial control. Despite SOCS1 expression, mycobacteria-infected macrophages responded to exogenously added IFN-γ. SOCS1 attenuated the expression of the majority of genes modulated by M. tuberculosis infection of macrophages. Using a conditional knockdown strategy in mice, we found that SOCS1 expression by macrophages hampered M. tuberculosis clearance early after infection in vivo in an IFN-γ-dependent manner. On the other hand, at later time points, SOCS1 expression by non-macrophage cells protected the host from infection-induced detrimental inflammation.

| S-EPMC3143647 | biostudies-literature

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