Anti-tuberculosis treatment strategies and drug development: challenges and priorities

Nature Reviews Microbiology, Год журнала: 2022, Номер 20(11), С. 685 - 701

Опубликована: Апрель 27, 2022

Despite two decades of intensified research to understand and cure tuberculosis disease, biological uncertainties remain hamper progress. However, owing collaborative initiatives including academia, the pharmaceutical industry non-for-profit organizations, drug candidate pipeline is promising. This exceptional success comes with inherent challenge prioritizing multidrug regimens for clinical trials revamping trial designs accelerate regimen development capitalize on discovery breakthroughs. Most wanted are markers progression from latent infection active pulmonary response predictors relapse, in vitro tools uncover synergies that translate clinically animal models reliably assess treatment shortening potential new regimens. In this Review, we highlight benefits challenges 'one-size-fits-all' duration versus individualized therapy based disease severity host pathogen characteristics, considering scientific operational perspectives.

Язык: Английский

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Applications of single-cell RNA sequencing in drug discovery and development

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(6), С. 496 - 520

Опубликована: Апрель 28, 2023

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery development. New opportunities emerging in target identification owing to improved disease understanding through cell subtyping, highly multiplexed functional genomics screens incorporating scRNA-seq enhancing credentialling prioritization. ScRNA-seq is also aiding selection relevant preclinical models providing new insights into mechanisms action. In clinical development, can inform decision-making via biomarker for patient stratification more precise monitoring response progression. Here, we illustrate how methods being applied key steps discuss ongoing challenges their implementation pharmaceutical industry. There have been significant recent advances development remarkable Ferran colleagues primarily pipeline, from decision-making. Ongoing potential future directions discussed.

Язык: Английский

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Immune cell interactions in tuberculosis

Cell, Год журнала: 2022, Номер 185(25), С. 4682 - 4702

Опубликована: Дек. 1, 2022

Язык: Английский

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T cell receptor repertoires associated with control and disease progression following Mycobacterium tuberculosis infection

Nature Medicine, Год журнала: 2023, Номер 29(1), С. 258 - 269

Опубликована: Янв. 1, 2023

Abstract Antigen-specific, MHC-restricted αβ T cells are necessary for protective immunity against Mycobacterium tuberculosis , but the ability to broadly study these responses has been limited. In present study, we used single-cell and bulk cell receptor (TCR) sequencing GLIPH2 algorithm analyze M. -specific sequences in two longitudinal cohorts, comprising 166 individuals with infection who progressed either ( n = 48) or controlled 118). We found 24 groups similar TCR-β sequences, predicted by have common TCR specificities, which were associated control of 17), others that progression disease 7). Using a genome-wide antigen screen, identified peptides targeted similarity enriched controllers progressors. propose antigens recognized can be considered as high-priority targets future vaccine development.

Язык: Английский

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Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis

Cell, Год журнала: 2023, Номер 186(25), С. 5536 - 5553.e22

Опубликована: Ноя. 28, 2023

Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying pathogenesis remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of IFN during Mtb infection in mice non-human primates, pDCs localize near human granulomas. Depletion reduces burdens, implicating pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs. Cell-type-specific disruption receptor suggests IFNs act on IMs inhibit control. Single-cell RNA sequencing (scRNA-seq) indicates IFN-responsive defective their response IFNγ, cytokine critical for propose pDC-derived permit bacterial replication, driving further recruitment active disease.

Язык: Английский

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Airway T cells are a correlate of i.v. Bacille Calmette-Guerin-mediated protection against tuberculosis in rhesus macaques

Cell Host & Microbe, Год журнала: 2023, Номер 31(6), С. 962 - 977.e8

Опубликована: Июнь 1, 2023

Язык: Английский

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Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(1)

Опубликована: Янв. 1, 2024

Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause this disease, many questions remain. In Review, we perform mechanistic interrogation activities that contribute to granuloma formation sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared divergent activities. We examine how Mycobacterium tuberculosis sensed system; initiated, formed, perpetuated compared sarcoidosis; role innate adaptive shaping processes. Finally, draw findings together around several recent high-resolution studies situ utilized latest advances single-cell technology combined spatial methods analyze plausible mechanisms. conclude an overall view sarcoidosis.

Язык: Английский

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How macrophage heterogeneity affects tuberculosis disease and therapy

Nature reviews. Immunology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Язык: Английский

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Intravenous BCG-mediated protection against tuberculosis requires CD4+ T cells and CD8α+ lymphocytes

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(4)

Опубликована: Янв. 17, 2025

Tuberculosis (TB) is a major health burden worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route and dose from 5 × 105 CFUs ID to 107 i.v. resulted prevention of Mycobacterium tuberculosis (Mtb) infection TB disease highly susceptible nonhuman primates. Identifying immune mechanisms protection following will facilitate development more effective vaccines against TB. Here, we depleted lymphocyte subsets prior during Mtb challenge BCG-vaccinated macaques identify those necessary for protection. Depletion adaptive CD4 T cells, but not CD8αβ loss with increased burdens dissemination, indicating cells are critical BCG-mediated unconventional CD8α-expressing lymphocytes (NK innate CD4+CD8α+ double-positive cells) abrogated most BCG-immunized macaques, supporting further investigation into which these cell contribute after vaccination.

Язык: Английский

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High-dose intravenous BCG vaccination induces enhanced immune signaling in the airways

Science Advances, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 1, 2025

Intradermal Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine, but it does not sufficiently protect adults against pulmonary tuberculosis. Recent studies in nonhuman primates show that intravenous BCG administration offers superior protection Mycobacterium tuberculosis ( Mtb ). We used single-cell analysis of bronchoalveolar lavage cells from rhesus macaques vaccinated via different routes and doses to identify alterations immune ecosystem airway following vaccination. Our findings reveal high-dose induces an influx polyfunctional T macrophages airways, with alveolar displaying a basal activation state absence purified protein derivative stimulation, defined part by interferon signaling. Enhanced intercellular signaling stronger helper 1–T 17 transcriptional responses were observed stimulation. These results suggest vaccination creates specialized environment primes for effective clearance.

Язык: Английский

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