Iron limitation in M. tuberculosis has broad impact on central carbon metabolism DOI Creative Commons
Monique E. Theriault, Davide Pisu, Kaley M. Wilburn

et al.

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: July 9, 2022

Abstract Mycobacterium tuberculosis ( Mtb ), the cause of human pulmonary disease (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids are actively catabolized by in vivo and fulfill major roles physiology pathogenesis. We conducted a high-throughput screen identify inhibitors survival its host macrophage. One hit compounds identified this screen, sAEL057, demonstrates highest activity on growth conditions where cholesterol was primary carbon source. Transcriptional functional data indicate sAEL057 limits ’s access iron acting as an chelator. Furthermore, pharmacological genetic inhibition acquisition results dysregulation catabolism, revealing previously unappreciated linkage between these pathways. Characterization sAEL057’s mode action argues metabolic regulation reveals vulnerabilities those pathways impact central metabolism.

Language: Английский

Immune evasion and provocation by Mycobacterium tuberculosis DOI Open Access
Pallavi Chandra, Steven J. Grigsby, Jennifer A. Philips

et al.

Nature Reviews Microbiology, Journal Year: 2022, Volume and Issue: 20(12), P. 750 - 766

Published: July 25, 2022

Language: Английский

Citations

322
Macrophage: A Cell With Many Faces and Functions in Tuberculosis DOI Creative Commons
Ahmad Faraz,

Anshu Rani,

Anwar Alam

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: May 6, 2022

Mycobacterium tuberculosis ( Mtb ) is the causative agent of human (TB) which primarily infects macrophages. Nearly a quarter world’s population infected latently by . Only around 5%–10% those develop active TB disease, particularly during suppressed host immune conditions or comorbidity such as HIV, hinting toward heterogeneity infection. The aerosolized first reaches lungs, and resident alveolar macrophages (AMs) are among cells to encounter Evidence suggests that early clearance infection associated with robust innate responses in In addition lung-resident macrophage subsets, recruited monocytes monocyte-derived (MDMs) have been suggested protective role , virtue its unique cell surface lipids secreted protein effectors, can evade killing preferentially establish niche within AMs. Continuous efforts delineate determinants defense mechanisms brought center stage crucial phenotypical variations for functional adaptations TB. morphological plasticity aid confining dissemination Mtb. However, hyperactivated state, virulence factors affect homeostasis may skew favor pathogen growth, causing This mini-review aimed at summarizing interplay pathomechanisms implications

Language: Английский

Citations

99
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

77
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
Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection DOI Creative Commons
Dat Mai, Ana N. Jahn,

Tara A. Murray

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(1), P. e1011871 - e1011871

Published: Jan. 18, 2024

Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in lung to encounter bacteria. We previously showed that AMs initially respond Mtb vivo by mounting cell-protective, rather than pro-inflammatory response. However, plasticity of initial AM response was unknown. Here, we characterize how previous exposure , either through subcutaneous vaccination with bovis (scBCG) or contained (coMtb) mimics aspects concomitant immunity, impacts AMs. find both scBCG and coMtb accelerate early innate cell activation recruitment generate stronger Within environment, from vaccinated mice mount robust interferon-associated response, while produce broader inflammatory is not dominated Interferon Stimulated Genes. Using scRNAseq, identify changes frequency phenotype airway-resident following exposure, enrichment for populations In contrast, minimal were found T dendritic after exposures. Ex stimulation Pam3Cys, LPS reveal exposures responses are cell-intrinsic changes. profiles unique each modality dependent on environment do emerge ex stimulation. Overall, our studies significant durable remodeling evidence AM-intrinsic contributions altered microenvironments. Comparisons between models highlight airway opportunities target their function host-directed therapies.

Language: Английский

Citations

26
Inducible antibacterial responses in macrophages DOI
Matthew J. Sweet, Divya Ramnath, Amit Singhal

et al.

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: 25(2), P. 92 - 107

Published: Sept. 18, 2024

Language: Английский

Citations

17
A pan-immune panorama of bacterial pneumonia revealed by a large-scale single-cell transcriptome atlas DOI Creative Commons
Kun Xiao, Yan Cao,

Zhihai Han

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 6, 2025

Abstract Bacterial pneumonia is a significant public health burden, contributing to substantial morbidity, mortality, and healthcare costs. Current therapeutic strategies beyond antibiotics adjuvant therapies are limited, highlighting the need for deeper understanding of disease pathogenesis. Here, we employed single-cell RNA sequencing 444,146 bronchoalveolar lavage fluid cells (BALFs) from large cohort 74 individuals, including 58 patients with mild ( n = 22) severe 36) diseases as well 16 healthy donors. Enzyme‐linked immunosorbent histological assays were applied validation within this cohort. The heterogeneity immune responses in bacterial was observed, distinct cell profiles related severity. Severe marked by an inflammatory cytokine storm resulting systemic upregulation S100A8 / A9 CXCL8 , primarily due specific macrophage neutrophil subsets. In contrast, exhibits effective humoral response characterized expansion T follicular helper 2 cells, facilitating B activation antibody production. Although both groups display exhaustion, cases maintained robust cytotoxic CD8 + function, potentially reflecting compensatory mechanism. Dysregulated contributed significantly pathogenesis disease. Immature neutrophils promote excessive inflammation suppress activation, while subset (Macro_03_M1) displaying features akin myeloid-derived suppressor (M-MDSCs) inflammation. Together, these findings highlight potential targets modulating improving clinical outcomes pneumonia.

Language: Английский

Citations

6
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
In the Thick of It: Formation of the Tuberculous Granuloma and Its Effects on Host and Therapeutic Responses DOI Creative Commons
Mark R. Cronan

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: March 7, 2022

The defining pathology of tuberculosis is the granuloma, an organized structure derived from host immune cells that surrounds infecting Mycobacterium . As location much bacteria in infected host, granuloma a central point interaction between and bacterium. This review describes signals cellular reprogramming drive formation. Further, as host-bacterial interactions, shapes disease outcome by altering responses bacterial susceptibility to antibiotic treatment, discussed herein. new understanding biology signaling behind it highlights potential for host-directed therapies targeting enhance access tuberculosis-specific responses.

Language: Английский

Citations

65