Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis DOI Creative Commons
Rocky Lai, Diana Gong, Travis Williams

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(13)

Published: May 18, 2023

Heterogeneity in human immune responses is difficult to model standard laboratory mice. To understand how host variation affects BCG-induced immunity against Mycobacterium tuberculosis, we studied 24 unique Collaborative Cross (CC) mouse strains, which differ primarily the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG, then challenged aerosolized M. tuberculosis. As BCG protects only half of tested, conclude that genetics has a major influence on tuberculosis infection, making it an important barrier vaccine-mediated protection. Importantly, efficacy dissociable inherent susceptibility TB. T cell was extensively characterized identify components associated protection stimulated by recalled after Mtb infection. Although considerable diversity observed, little impact composition cells lung Instead, variability largely shaped genetics. BCG-elicited TB correlated changes function. Thus, mice can be used define correlates vaccine strategies protect larger fraction genetically diverse individuals instead optimizing for single genotype.

Language: Английский

Anti-tuberculosis treatment strategies and drug development: challenges and priorities DOI Creative Commons
Véronique Dartois, Eric J. Rubin

Nature Reviews Microbiology, Journal Year: 2022, Volume and Issue: 20(11), P. 685 - 701

Published: April 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.

Language: Английский

Citations

327
Applications of single-cell RNA sequencing in drug discovery and development DOI Creative Commons
Bram Van de Sande, Joon Sang Lee, Euphemia Mutasa-Gottgens

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 496 - 520

Published: April 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.

Language: Английский

Citations

205
Immune cell interactions in tuberculosis DOI Creative Commons
JoAnne L. Flynn, John Chan

Cell, Journal Year: 2022, Volume and Issue: 185(25), P. 4682 - 4702

Published: Dec. 1, 2022

Language: Английский

Citations

76
T cell receptor repertoires associated with control and disease progression following Mycobacterium tuberculosis infection DOI Creative Commons
Munyaradzi Musvosvi, Huang Huang, Chunlin Wang

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(1), P. 258 - 269

Published: Jan. 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.

Language: Английский

Citations

60
Airway T cells are a correlate of i.v. Bacille Calmette-Guerin-mediated protection against tuberculosis in rhesus macaques DOI Creative Commons
Patricia A. Darrah, Joseph J. Zeppa, Chuangqi Wang

et al.

Cell Host & Microbe, Journal Year: 2023, Volume and Issue: 31(6), P. 962 - 977.e8

Published: June 1, 2023

Language: Английский

Citations

53
Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis DOI Creative Commons
Dmitri I. Kotov, Ophelia V. Lee, Stefan A. Fattinger

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(25), P. 5536 - 5553.e22

Published: Nov. 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.

Language: Английский

Citations

53
Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis DOI Creative Commons
Praveen Weeratunga, David R. Möller, Ling‐Pei Ho

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(1)

Published: Jan. 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.

Language: Английский

Citations

26
How macrophage heterogeneity affects tuberculosis disease and therapy DOI
David G. Russell, Nelson V. Simwela,

Joshua T. Mattila

et al.

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: Английский

Citations

4
High-dose intravenous BCG vaccination induces enhanced immune signaling in the airways DOI Creative Commons
Joshua M. Peters, Edward B. Irvine, Mohau S. Makatsa

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 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.

Language: Английский

Citations

2
Intravenous BCG-mediated protection against tuberculosis requires CD4+ T cells and CD8α+ lymphocytes DOI
Andrew Simonson, Joseph J. Zeppa, Allison N. Bucşan

et al.

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(4)

Published: Jan. 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.

Language: Английский

Citations

2