Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(5), С. 381 - 403

Опубликована: Фев. 28, 2024

Язык: Английский

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Foam Cells: One Size Doesn’t Fit All

Trends in Immunology, Год журнала: 2019, Номер 40(12), С. 1163 - 1179

Опубликована: Ноя. 12, 2019

Язык: Английский

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Caseum: a Niche for Mycobacterium tuberculosis Drug-Tolerant Persisters

Clinical Microbiology Reviews, Год журнала: 2020, Номер 33(3)

Опубликована: Март 31, 2020

Caseum, the central necrotic material of tuberculous lesions, is a reservoir drug-recalcitrant persisting mycobacteria. Caseum found in closed nodules and open cavities connecting with an airway. Several commonly accepted characteristics caseum were established during preantibiotic era, when autopsies deceased tuberculosis (TB) patients common but methodologies limited. These pioneering studies generated concepts such as acidic pH, low oxygen tension, paucity nutrients being drivers nonreplication persistence caseum.

Язык: Английский

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Mycobacterium tuberculosis Infection-Driven Foamy Macrophages and Their Implications in Tuberculosis Control as Targets for Host-Directed Therapy

Frontiers in Immunology, Год журнала: 2020, Номер 11

Опубликована: Май 12, 2020

Tuberculosis (TB) is a leading cause of death worldwide following infection with Mycobacterium tuberculosis (Mtb), 1.5 million deaths from this disease reported in 2018. Once the bacilli are inhaled, alveolar and interstitial macrophages become infected Mtb differentiate into lipid-laden foamy to lung inflammation. Thus, presence hallmark TB granuloma; these Mtb-infected major niche for survival. The fate pathogenesis likely determined by altered function macrophages, which initiate mediate TB-related As play central roles Mtb, they may be important development host-directed therapy against TB. Here, we summarize discuss current understanding alterations regulation infection-induced immune responses. Metabolic reprogramming or virulence factors also summarized. Furthermore, review therapeutic interventions targeting responses metabolic pathways, vitro, vivo, clinical studies. This will further our both targets

Язык: Английский

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Immunometabolism of Phagocytes During Mycobacterium tuberculosis Infection

Frontiers in Molecular Biosciences, Год журнала: 2019, Номер 6

Опубликована: Окт. 14, 2019

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains as a leading killer among infectious diseases worldwide. The nature of the host immune response dictates whether initial Mtb infection is cleared or progresses towards active disease, and ultimately determined intricate host-pathogen interactions that are yet to be fully understood. early mediated innate cells, including macrophages neutrophils can phagocytose mount an antimicrobial response. However, exploit these cells for its survival dissemination. Recently, it has become clear metabolic remodeling interconnected, which highlighted rapid evolution interdisciplinary field immunometabolism. It been proposed net outcome – clearance chronic disease - likely result combined immunologic activities cells. Indeed, activated have strikingly different requirements than naïve/non-infected Macrophages Mtb-derived molecules upon phagocytosis acquire phenotype similar M1 with elevated production pro-inflammatory rely on glycolysis pentose phosphate pathway meet their bioenergetic requirements. In macrophages, oxidative phosphorylation fatty acid oxidation dampened. non-infected/naive, M2-type anti-inflammatory derive energy from oxidation. Similar adaptations also occur in other phagocytes, dendritic infection. This reprogramming during differentially regulate effector functions, such cytokines chemokines, response, all determine Mtb-host within granulomas. this review, we describe key bolstering discuss phagocytes We focused major regulators involved reprogramming, hypoxia-inducible factor-1, mammalian target rapamycin, cellular myelocytomatosis, peroxisome proliferator-activator receptors, sirtuins, arginases, inducible nitric synthase sphingolipids.

Язык: Английский

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Immunometabolism during Mycobacterium tuberculosis Infection

Trends in Microbiology, Год журнала: 2020, Номер 28(10), С. 832 - 850

Опубликована: Май 11, 2020

Язык: Английский

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Not too fat to fight: The emerging role of macrophage fatty acid metabolism in immunity to Mycobacterium tuberculosis

Immunological Reviews, Год журнала: 2021, Номер 301(1), С. 84 - 97

Опубликована: Фев. 8, 2021

Abstract While the existence of a special relationship between Mycobacterium tuberculosis (Mtb) and host lipids has long been known, it remains challenging enigma. It was clearly established that Mtb requires fatty acids (FAs) cholesterol to produce energy, build its distinctive lipid‐rich cell wall, lipid virulence factors. also observed in infected hosts, constantly resides FA‐rich environment pathogen contributes generate by inducing lipid‐laden “foamy” phenotype macrophages. These observations proximity droplets phagosomes containing bacteria within macrophages gave rise hypothesis reprograms metabolism ensure continuous supply essential nutrients long‐term persistence vivo. However, recent studies question this principle indicating Mtb‐infected macrophages, droplet formation prevents bacterial acquisition FAs while supporting production FA‐derived protective mediators. Further, vivo investigations reveal discrete macrophage phenotypes linking FA metabolisms intracellular pathogen. Notably, storage characterizes both controlling infection dormant Mtb. In review, we integrate findings from immunological microbiological illustrating new concept cytoplasmic accumulation is metabolic adaptation infection, which potentiates their antimycobacterial responses forces shift into fat‐saving, survival mode.

Язык: Английский

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The cause–effect relation of tuberculosis on incidence of diabetes mellitus

Frontiers in Cellular and Infection Microbiology, Год журнала: 2023, Номер 13

Опубликована: Июнь 26, 2023

Tuberculosis (TB) is one of the oldest human diseases and major causes mortality morbidity across Globe. Mycobacterium tuberculosis (Mtb), causal agent TB most successful pathogens known to mankind. Malnutrition, smoking, co-infection with other like immunodeficiency virus (HIV), or conditions diabetes further aggravate pathogenesis. The association between type 2 mellitus (DM) well immune-metabolic changes during are cause increased susceptibility tuberculosis. Many epidemiological studies suggest occurrence hyperglycemia active leading impaired glucose tolerance insulin resistance. However, mechanisms underlying these effects not understood. In this review, we have described possible factors inflammation, host metabolic triggered by that could contribute development resistance diabetes. We also discussed therapeutic management TB, which may help in designing future strategies cope TB-DM cases.

Язык: Английский

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A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(6)

Опубликована: Фев. 9, 2023

Induction of lipid-laden foamy macrophages is a cellular hallmark tuberculosis (TB) disease, which involves the transformation infected phagolysosomes from site killing into nutrient-rich replicative niche. Here, we show that terpenyl nucleoside shed Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with nucleoside-producing M. intralysosomal peribacillary patterns matched both molecules subcellular locations known Lipidomics showed 1-TbAd induced triacylglycerides cholesterylesters increased growth under conditions restricted access Furthermore, lipidomics identified 1-TbAd-induced substrates define Gaucher's Wolman's other inborn diseases. These data identify genetic molecular causes tuberculosis-induced failure, successful testing an agonist TRPML1 calcium channels reverses cells. establish host-directed functions orphan effector molecule promotes survival macrophages, providing upstream cause detailed picture lysosome failure

Язык: Английский

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Polyphosphate kinase-1 regulates bacterial and host metabolic pathways involved in pathogenesis of Mycobacterium tuberculosis

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(2)

Опубликована: Янв. 3, 2024

Inorganic polyphosphate (polyP) is primarily synthesized by Polyphosphate Kinase-1 (PPK-1) and regulates numerous cellular processes, including energy metabolism, stress adaptation, drug tolerance, microbial pathogenesis. Here, we report that polyP interacts with acyl CoA carboxylases, enzymes involved in lipid biosynthesis Mycobacterium tuberculosis . We show deletion of ppk-1 M. results transcriptional metabolic reprogramming. In comparison to the parental strain, Δ mutant strain had reduced levels virulence-associated lipids such as PDIMs TDM. also observed deficiency associated enhanced phagosome–lysosome fusion infected macrophages attenuated growth mice. Host RNA-seq analysis revealed decreased transcripts encoding for proteins either type I interferon signaling or formation foamy lungs mutant–infected mice relative strain–infected animals. Using target-based screening molecular docking, have identified raloxifene hydrochloride a broad-spectrum PPK-1 inhibitor. significantly activity isoniazid, bedaquiline, pretomanid against macrophages. Additionally, inhibited This an in-depth study provides mechanistic insights into regulation mycobacterial pathogenesis deficiency.

Язык: Английский

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