Human innate Mycobacterium tuberculosis-reactive alphabetaTCR+ thymocytes.
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ABSTRACT:
SUBMITTER: Gold MC
PROVIDER: S-EPMC2242840 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To determine the mechanisms that mediate resistance to Mycobacterium tuberculosis (M. tuberculosis) infection in household contacts (HHCs) of patients with tuberculosis (TB), we followed 452 latent TB infection-negative (LTBI-) HHCs for 2 years. Those who remained LTBI- throughout the study were identified as nonconverters. At baseline, nonconverters had a higher percentage of CD14+ and CD3-CD56+CD27+CCR7+ memory-like natural killer (NK) cells. Using a whole-transcriptome and metabolomic approach, we identified deoxycorticosterone acetate as a metabolite with elevated concentrations in the plasma of nonconverters, and further studies showed that this metabolite enhanced glycolytic ATP flux in macrophages and restricted M. tuberculosis growth by enhancing antimicrobial peptide production through the expression of the surface receptor sialic acid binding Ig-like lectin-14. Another metabolite, 4-hydroxypyridine, from the plasma of nonconverters significantly enhanced the expansion of memory-like NK cells. Our findings demonstrate that increased levels of specific metabolites can regulate innate resistance against M. tuberculosis infection in HHCs of patients with TB who never develop LTBI or active TB.
| S-EPMC9746823 | biostudies-literature
Project description:Mycobacterium tuberculosis (M. tuberculosis) is an intracellular pathogen that primarily infects macrophages. Despite a robust anti-mycobacterial response, many times macrophages are unable to control M. tuberculosis. The purpose of this study was to investigate the mechanism by which the immunoregulatory cytokine IL-27 inhibits the anti-mycobacterial activity of primary human macrophages. We found concerted production of IL-27 and anti-mycobacterial cytokines by M. tuberculosis-infected macrophages in a toll-like receptor (TLR) dependent manner. Notably, IL-27 suppressed the production of anti-mycobacterial cytokines TNFα, IL-6, IL-1β, and IL-15 by M. tuberculosis-infected macrophages. IL-27 limits the anti-mycobacterial activity of macrophages by reducing Cyp27B, cathelicidin (LL-37), LC3B lipidation, and increasing IL-10 production. Furthermore, neutralizing both IL-27 and IL-10 increased the expression of proteins involved in LC3-associated phagocytosis (LAP) pathway for bacterial clearance, namely vacuolar-ATPase, NOX2, and RUN-domain containing protein RUBCN. These results implicate IL-27 is a prominent cytokine that impedes M. tuberculosis clearance.
| S-EPMC10052773 | biostudies-literature
Project description:BackgroundAs a species, Mycobacterium tuberculosis is more diverse than previously thought. In particular, the Beijing family of M. tuberculosis strains is spreading and evaluating throughout the world and this is giving rise to public health concerns. Genetic diversity within this family has recently been delineated further and a specific genotype, called Bmyc10, has been shown to represent over 60% of all Beijing clinical isolates in several parts of the world. How the host immune system senses and responds to various M. tuberculosis strains may profoundly influence clinical outcome and the relative epidemiological success of the different mycobacterial lineages. We hypothesised that the success of the Bmyc10 group may, at least in part, rely upon its ability to alter innate immune responses and the secretion of cytokines and chemokines by host phagocytes.Methodology/principal findingsWe infected human macrophages and dendritic cells with a collection of genetically well-defined M. tuberculosis clinical isolates belonging to various mycobacterial families, including Beijing. We analyzed cytokine and chemokine secretion on a semi-global level using antibody arrays allowing the detection of sixty-five immunity-related soluble molecules. Our data indicate that Beijing strains induce significantly less interleukin (IL)-6, tumor necrosis factor (TNF), IL-10 and GRO-? than the H37Rv reference strain, a feature that is variously shared by other modern and ancient M. tuberculosis families and which constitutes a signature of the Beijing family as a whole. However, Beijing strains did not differ relative to each other in their ability to modulate cytokine secretion.Conclusions/significanceOur results confirm and expand upon previous reports showing that M. tuberculosis Beijing strains in general are poor in vitro cytokine inducers in human phagocytes. The results suggest that the epidemiological success of the Beijing Bmyc10 is unlikely to rely upon any specific ability of this group of strains to impair anti-mycobacterial innate immunity.
| S-EPMC2963601 | biostudies-literature
Project description:Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for cross talk or synergy between bacterium- and mitochondrion-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking, and intriguing, in the context of infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages, leading to metabolic changes and triggering potent innate immune responses. Research from our laboratories and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyperactivating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrion-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.
| S-EPMC8090963 | biostudies-literature
Project description:Mycobacterium tuberculosis is a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by which M. tuberculosis circumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate of M. tuberculosis of the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-?B, a key regulator of innate immunity. We identified several M. tuberculosis mutants inducing a NF-?B activation stronger than that of the wild-type strain. One of these mutants was found to be deficient for the synthesis of cell envelope glycolipids, namely sulfoglycolipids, suggesting that the latter can interfere with innate immune responses. Using natural and synthetic molecular variants, we determined that sulfoglycolipids inhibit NF-?B activation and subsequent cytokine production or costimulatory molecule expression by acting as competitive antagonists of Toll-like receptor 2, thereby inhibiting the recognition of M. tuberculosis by this receptor. Our study reveals that producing glycolipid antagonists of pattern recognition receptors is a strategy used by M. tuberculosis to undermine innate immune defense. Sulfoglycolipids are major and specific lipids of M. tuberculosis, considered for decades as virulence factors of the bacilli. Our study uncovers a mechanism by which they may contribute to M. tuberculosis virulence.
| S-EPMC5651758 | biostudies-literature
Project description:The bacteriostatic and bactericidal effects and the corresponding expression profiles of Mycobacterium tuberculosis to representative oxidative and nitrosative stresses were investigated by growth and survival studies and whole genome expression analysis. The response of M. tuberculosis to a range of hydrogen peroxide (H2O2) concentrations tended to fall into three distinct categories: (1) low level exposure resulted in induction of few H2O2 sensitive genes, (2) intermediate exposure resulted in massive transcriptional changes without an effect on growth or survival, and (3) high exposure resulted in a muted transcriptional response and eventual death. Nitric oxide (NO) exposure initiated much of the same transcriptional response as H2O2. However, unlike H2O2 exposure, NO exposure affected a dose-dependent bacteriostatic activity without killing and induction of dormancy-related genes. Included in the shared response to H2O2 and NO was the induction of genes encoding oxidative stress detoxification and iron-sulfur cluster repair functions. Expression of several key oxidative stress defense genes was constitutive, or increased moderately from an already elevated level, suggesting bacilli that are continually primed for oxidative stress defense. Deletion of the known oxidative stress responsive regulator, FurA, resulted in the constitutive expression of furA, katG, and Rv1907c; while other genes do not appear to be solely controlled by FurA. In contrast to Escherichia coli, M. tuberculosis appears highly resistant to DNA damage-dependent killing caused by low mill molar levels of H2O2. Furthermore, instead of limiting access to iron to prevent hydroxyl radical formation from H2O2 and thus DNA damage, M. tuberculosis induced iron uptake genes in response to H2O2 and NO.
2010-05-18 | GSE16146 | GEO
Project description:Early events in the human airways determining whether exposure to Mycobacterium tuberculosis (Mtb) results in acquisition of infection are poorly understood. Epithelial cells are the dominant cell type in the lungs, but little is known about their role in tuberculosis. We hypothesised that human primary airway epithelial cells are part of the first line of defense against Mtb-infection and contribute to the protective host response in the human respiratory tract. We modelled these early airway-interactions with human primary bronchial epithelial cells (PBECs) and alveolar macrophages. By combining in vitro infection and transwell co-culture models with a global transcriptomic approach, we identified PBECs to be inert to direct Mtb-infection, yet to be potent responders within an Mtb-activated immune network, mediated by IL1β and type I interferon (IFN). Activation of PBECs by Mtb-infected alveolar macrophages and monocytes increased expression of known and novel antimycobacterial peptides, defensins and S100-family members and epithelial-myeloid interactions further shaped the immunological environment during Mtb-infection by promoting neutrophil influx. This is the first in depth analysis of the primary epithelial response to infection and offers new insights into their emerging role in tuberculosis through complementing and amplifying responses to Mtb.
| S-EPMC5605092 | biostudies-literature
Project description:The bacteriostatic and bactericidal effects and the transcriptional response of Mycobacterium tuberculosis to representative oxidative and nitrosative stresses were investigated by growth and survival studies and whole genome expression analysis. The M. tuberculosis reaction to a range of hydrogen peroxide (H(2)O(2)) concentrations fell into three distinct categories: (1) low level exposure resulted in induction of a few highly sensitive H(2)O(2)-responsive genes, (2) intermediate exposure resulted in massive transcriptional changes without an effect on growth or survival, and (3) high exposure resulted in a muted transcriptional response and eventual death. M. tuberculosis appears highly resistant to DNA damage-dependent, mode-one killing caused by low millimolar levels of H(2)O(2) and only succumbs to overwhelming levels of oxidative stress observed in mode-two killing. Nitric oxide (NO) exposure initiated much the same transcriptional response as H(2)O(2). However, unlike H(2)O(2) exposure, NO exposure induced dormancy-related genes and caused dose-dependent bacteriostatic activity without killing. Included in the large shared response to H(2)O(2) and NO was the induction of genes encoding iron-sulfur cluster repair functions including iron acquisition. Stress regulons controlled by IdeR, Sigma H, Sigma E, and FurA comprised a large portion of the response to both stresses. Expression of several oxidative stress defense genes was constitutive, or increased moderately from an already elevated constitutive level, suggesting that bacilli are continually primed for oxidative stress defense.
| S-EPMC3119406 | biostudies-literature
Project description:The bacteriostatic and bactericidal effects and the corresponding expression profiles of Mycobacterium tuberculosis to representative oxidative and nitrosative stresses were investigated by growth and survival studies and whole genome expression analysis. The response of M. tuberculosis to a range of hydrogen peroxide (H2O2) concentrations tended to fall into three distinct categories: (1) low level exposure resulted in induction of few H2O2 sensitive genes, (2) intermediate exposure resulted in massive transcriptional changes without an effect on growth or survival, and (3) high exposure resulted in a muted transcriptional response and eventual death. Nitric oxide (NO) exposure initiated much of the same transcriptional response as H2O2. However, unlike H2O2 exposure, NO exposure affected a dose-dependent bacteriostatic activity without killing and induction of dormancy-related genes. Included in the shared response to H2O2 and NO was the induction of genes encoding oxidative stress detoxification and iron-sulfur cluster repair functions. Expression of several key oxidative stress defense genes was constitutive, or increased moderately from an already elevated level, suggesting bacilli that are continually primed for oxidative stress defense. Deletion of the known oxidative stress responsive regulator, FurA, resulted in the constitutive expression of furA, katG, and Rv1907c; while other genes do not appear to be solely controlled by FurA. In contrast to Escherichia coli, M. tuberculosis appears highly resistant to DNA damage-dependent killing caused by low mill molar levels of H2O2. Furthermore, instead of limiting access to iron to prevent hydroxyl radical formation from H2O2 and thus DNA damage, M. tuberculosis induced iron uptake genes in response to H2O2 and NO. Set of arrays that are part of repeated experiments Compound Based Treatment: H2O2 or DETA/NO treatment
2010-05-18 | E-GEOD-16146 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (Mtb) infection can be cleared by the innate immune system before the initiation of an adaptive immune response. This innate protection requires a variety of robust cell autonomous responses from many different host immune cell types. However, Mtb has evolved strategies to circumvent some of these defences. In this mini-review, we discuss these host-pathogen interactions with a focus on studies performed in human cells and/or supported by human genetics studies (such as genome-wide association studies).
| S-EPMC4832344 | biostudies-other