Type I Interferon Exacerbates Mycobacterium tuberculosis Induced Human Macrophage Death
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PROVIDER: PRJNA1098878 | ENA |
REPOSITORIES: ENA
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Project description:Type I Interferon Exacerbates Mycobacterium tuberculosis Induced Human Macrophage Death
| PRJNA1098879 | ENA
Project description:Type I interferons (IFN-I) are implicated in exacerbation of tuberculosis (TB), but the mechanisms are unclear. Mouse macrophages infected with Mycobacterium tuberculosis (Mtb) produce IFN-I, which contributes to their death. Here we investigate whether the same is true for human monocyte-derived macrophages (MDM). MDM prepared by a conventional method markedly upregulate interferon-stimulated genes (ISGs) upon Mtb infection, while MDM prepared to better restrict Mtb do so much less. A mixture of antibodies inhibiting IFN-I signaling prevents ISG induction. Surprisingly, secreted IFN-I are undetectable until nearly two days after ISG induction. These same antibodies do not diminish Mtb-infected MDM death. MDM induce ISGs in response to picogram/mL levels of exogenous IFN-I while depleting similar quantities from the medium. Exogenous IFN-I increase the proportion of dead MDM. We speculate that Mtb-infected MDM produce and respond to minute levels of IFN-I, and that only some of the resultant signaling is susceptible to neutralizing antibodies. Many types of cells may secrete IFN-I in patients with TB, where IFN-I is likely to promote the death of infected macrophages.
| S-EPMC11239827 | biostudies-literature
Project description:Mycobacterium tuberculosis and macrophage response
| PRJNA100713 | ENA
Project description:Inflammation is critical for controlling infections but can cause disease when unchecked. For tuberculosis, the leading cause of death by infection, neutrophil-dominated inflammation is associated with disease progression, emphasizing the need to understand how neutrophil functions are regulated during Mycobacterium tuberculosis infection. Atg5 was the first gene shown to specifically function within neutrophils to promote control of M. tuberculosis. ATG5 is best studied for its role in autophagy, however, the protective activity of ATG5 in neutrophils was unexpectedly independent of other autophagy proteins and remained elusive. We report that ATG5 is required in neutrophils to suppress type I interferon-induced neutrophil extracellular trap (NET) release and swarming during M. tuberculosis infection. Elevated NET release contributes to the early susceptibility of Atg5fl/fl-LysM-Cre mice during infection. These findings identify ATG5 as a master regulator of how type I interferon influences neutrophil responses during infection, revealing a new potential target for host-directed therapies.
2025-03-07 | GSE280193 | GEO
Project description:Multifaceted dysfunction of infant airway macrophages in response to Mycobacterium tuberculosis
2025-01-23 | E-MTAB-7679 | ExpressionAtlas
Project description:Extracellular Mycobacterium tuberculosis (Mtb) aggregates can evade phagocytosis and intracellular host-cell defenses by inducing macrophage killing. We showed that Mtb aggregates require a functional ESX-1 type VII secretion system and production of the surface-exposed lipid phthiocerol dimycocerosate (PDIM) to induce cell death upon contact with macrophages. We used quantitative proteomics to compare the secretome of a panel of Mtb mutant strains that induce or do not induce macrophage death and identified secreted bacteria factors involved in macrophage death induction.
2023-03-16 | PXD035080 | Pride
Project description:Extracellular Mycobacterium tuberculosis (Mtb) aggregates can evade phagocytosis and intracellular host-cell defenses by inducing macrophage killing. We showed that Mtb aggregates require a functional ESX-1 type VII secretion system to induce cell death upon contact with macrophages. We used quantitative proteomics to compare the secretome of a esxA mutant strain with the wild type reference to identify secreted bacteria factors involved in macrophage death induction.
2023-03-16 | PXD035082 | Pride
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:Mycobacterial arabinogalactan (AG) is an essential cell wall component of Mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Yet, it is unclear whether mycobacterial AG is a pathogen-associated molecular pattern (PAMP) with an elusive pattern recognition receptor (PRR). Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibited cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increased survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacted with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associated with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocked AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravated the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.
2021-02-17 | GSE166850 | GEO
Project description:We report here a modified protocol for generating homogenous populations of macrophage-like cells from human embryonic stem cells. The induced macrophages, referred to as iMAC, presented similar transcriptomic profiles and characteristic immunological features of classical macrophages and were permissive to viral and bacterial infection, in particular Mycobacterium tuberculosis (Mtb). Their production was amenable to scale up and the resulting cells suitable for high-throughput screening.
2019-10-31 | GSE138398 | GEO