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

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

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Antigen-specific B cells direct T follicular-like helper cells into lymphoid follicles to mediate Mycobacterium tuberculosis control

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(5), P. 855 - 868

Published: April 3, 2023

Language: Английский

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Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 16, 2025

Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading augmented inflammatory responses and pathogen clearance secondary exposure. While differentiation of hematopoietic stem (HSCs) reprogramming bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling cellular architecture within tissue during remains underexplored. Here, we study effects peritoneal Bacillus Calmette–Guérin (BCG) administration find TI-mediated protection in spleen against a subsequent heterologous infection by Gram-negative Salmonella Typhimurium ( S .Tm). Utilizing single cell RNA-sequencing flow cytometry, discerned STAT1-regulated genes TI-associated resident recruited splenic myeloid populations. The temporal dynamics were further elucidated, revealing both early delayed subsets with time-dependent, cell-type-specific STAT1 signatures. Using lineage tracing, that tissue-resident red pulp macrophages (RPM), initially depleted BCG exposure, restored from tissue-trained, self-renewing marrow-derived progenitors, fostering long lasting local defense. Early inhibition activation, using JAK-STAT inhibitors, reduces RPM loss recruitment trained monocytes. Our suggests window soon after vaccination, which STAT1-dependent activation long-lived mediates localized protection.

Language: Английский

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Inhibition of indoleamine dioxygenase leads to better control of tuberculosis adjunctive to chemotherapy

JCI Insight, Journal Year: 2023, Volume and Issue: 8(2)

Published: Jan. 23, 2023

The expression of indoleamine 2,3-dioxygenase (IDO), a robust immunosuppressant, is significantly induced in macaque tuberculosis (TB) granulomas, where it expressed on IFN-responsive macrophages and myeloid-derived suppressor cells. IDO also highly human TB products its activity are detected patients with TB. In vivo blockade resulted the reorganization granuloma substantially greater T cells being recruited to core lesions. This correlated better immune control reduced lung M. burdens. To study if strategy can be translated bona fide host-directed therapy clinical setting TB, we studied effect inhibitor 1-methyl-d-tryptophan adjunctive suboptimal anti-TB chemotherapy. While two-thirds controls one-third chemotherapy-treated animals progressed active inhibition same protected macaques from as measured by clinical, radiological, microbiological attributes. Although chemotherapy improved proliferative cell responses, further enhanced recruitment effector lung. These results strongly suggest possibility that attempted trials.

Language: Английский

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Identification of apoptosis-related gene signatures as potential biomarkers for differentiating active from latent tuberculosis via bioinformatics analysis

Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 19, 2024

Background Apoptosis is associated with the pathogenesis of Mycobacterium tuberculosis infection. This study aims to identify apoptosis-related genes as biomarkers for differentiating active (ATB) from latent infection (LTBI). Methods The (TB) datasets (GSE19491, GSE62525, and GSE28623) were downloaded Gene Expression Omnibus (GEO) database. diagnostic ATB LTBI identified by combining data protein-protein interaction network, differentially expressed gene, Weighted Co-Expression Network Analysis (WGCNA), receiver operating characteristic (ROC) analyses. Machine learning algorithms employed validate ability biomarkers. Enrichment analysis was established, potential drugs predicted. association between N6-methyladenosine (m6A) or 5-methylated cytosine (m5C) regulators evaluated. Results Six including CASP1, TNFSF10, CASP4, CASP5, IFI16 , ATF3 obtained LTBI. They showed strong performances, area under ROC (AUC) values > 0.7. demonstrated that involved in immune inflammation responses. Furthermore, 24 drugs, progesterone emricasan, correlation revealed positively correlated most m6A m5C regulators. Conclusion six ARGs can serve effective provide insight into

Language: Английский

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Heterogeneity in immune cell composition is associated with Mycobacterium tuberculosis replication at the granuloma level

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 26, 2024

The control of bacterial growth is key to the prevention and treatment tuberculosis (TB). Granulomas represent independent foci host immune response that present heterogeneous capacity for growth. At whole tissue level, B cells CD4 or CD8 T have an established role in protection against TB. Immune interact within each granuloma response, but impact composition on replication remains unknown. Here we investigate associations between cell composition, including cell, CD4, cells, state replicating Mycobacterium ( Mtb) granuloma. A measure ribosomal RNA synthesis, RS ratio®, represents a proxy Mtb at level. We adapted ratio through use situ hybridization, identify non-replicating designated applied regression model characterize populations respective In evaluation nearly 200 granulomas, identified heterogeneity both proportion bacteria. found clear evidence directional . Controlling vaccination status endpoint post-infection, granulomas with lower higher counts are associated percent Conversely, changes proportions were little change replication. This study establishes across demonstrating certain types differentially These data suggest level may be imperative identifying correlates protection.

Language: Английский

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Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

Published: Jan. 7, 2025

Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading augmented inflammatory responses and pathogen clearance secondary exposure. While differentiation of hematopoietic stem (HSCs) reprogramming bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling cellular architecture within tissue during remains underexplored. Here, we study effects peritoneal Bacillus Calmette–Guérin (BCG) administration find TI-mediated protection in spleen against a subsequent heterologous infection by Gram-negative Salmonella Typhimurium ( S .Tm). Utilizing single cell RNA-sequencing flow cytometry, discerned STAT1-regulated genes TI-associated resident recruited splenic myeloid populations. The temporal dynamics were further elucidated, revealing both early delayed subsets with time-dependent, type-specific STAT1 signatures. Using lineage tracing, that tissue-resident red pulp macrophages (RPM), initially depleted BCG exposure, restored from tissue-trained, self-renewing marrow-derived progenitors, fostering long lasting local defense. Early inhibition activation, using JAK-STAT inhibitors, reduces RPM loss recruitment trained monocytes. Our suggests window soon after vaccination, which STAT1-dependent activation long-lived mediates localized protection.

Language: Английский

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Single-cell map of innate-like lymphocyte response to Francisella tularensis infection reveals interleukin-17-dependent protection by MAIT cells

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 111810 - 111810

Published: Jan. 18, 2025

Early immune dynamics during the initiation of fatal tularemia caused by Francisella tularensis infection remain unknown. Unto that end, we generated a transcriptomic map at single-cell resolution innate-like lymphocyte responses to F. live vaccine strain (LVS) mice. We found both interferon-γ (IFN-γ)-producing type 1 and interleukin-17 (IL-17)-producing 3 lymphocytes expanded in infected lungs. Natural killer (NK) NKT cells drove response, whereas mucosal-associated invariant T (MAIT) γδ response. Furthermore, tularemia-like disease resistant cell-deficient, Cd1d -/- mice accumulated more MAIT1 cells, MAIT17 with hybrid phenotype between than wild-type Critically, adoptive transfer LVS-activated MAIT from mice, which were enriched was sufficient protect LVS-susceptible, immunodeficient RAG2 severe LVS infection-inflicted pathology. Collectively, our findings position as potential mediators IL-17-dependent protection pulmonary disease.

Language: Английский

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Single-cell transcriptomics identifies a dampened neutrophil function and accentuated T-cell cytotoxicity in tobacco flavored e-cigarette exposed mouse lungs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Abstract E-cigarettes (e-cigs) are a public health concern for young adults due to their popularity and evidence increased oxidative stress immunotoxicity. Yet an extensive study defining the cell-specific immune changes upon exposure flavored e-cigs remains elusive. To understand immunological lung landscape acute nose-only of C57BL/6J e-cig aerosols we performed single-cell RNA sequencing (scRNA seq). scRNA profiles 71,725 cells were generated from control treatment groups (n=2/sex/group). A distinct phenotype Ly6G-neutrophils was identified in lungs exposed tobacco aerosol which demonstrated dampened IL-1 mediated pattern recognition signaling as compared air controls. Differential gene expression analyses dysregulation T-cell pro-inflammation ( Cct7 , Cct8 ) stress-response signals Neurl3 Stap1 Cirbp Htr2c) mice aerosols, with pronounced effects flavor. Flow cytometry cytokine/chemokine assessments within corroborated seq data, demonstrating significant increase percentages levels associated cytokine/chemokines tobacco-flavored mice. Increased Klra4 Klra8 also suggest enhanced natural killer (NK) cell activity this mouse group. Overall, is pilot identifying that may be responsible innate responses heightened cytotoxicity In addition, provide preliminary sex-specific transcriptional aerosol, area warrants further study.

Language: Английский

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Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 25, 2025

The need for novel vaccination strategies to control tuberculosis (TB) is underscored by the limited and variable efficacy of currently licensed vaccine, Bacille Calmette-Guerin (BCG). SigH critical Mycobacterium (Mtb) mitigate oxidative stress, in its absence Mtb unable scavenge host oxidative/nitrosative bursts. MtbΔsigH (ΔsigH) isogenic mutant induces signatures innate immunity macrophages protects rhesus macaques from a lethal challenge. To understand immune mechanisms protection via mucosal with ΔsigH, we employed resistant cynomolgus macaque model; our results show that ΔsigH significantly against challenge this species. ΔsigH-vaccinated are devoid granulomas instead generate inducible bronchus associated lymphoid structures, robust antigen-specific CD4+ CD8+ T cell responses, driven hyper-immune, trained immunity-like phenotype enhanced antigen presentation. Correlates include gene activation, IFNG production, including IFN-responsive, activated cells, concomitant suppression IDO+ Type I IFN-responsive macrophage recruitment. Thus, promising lead candidate further development as an antitubercular vaccine. Authors employ model explore protective potential ΔsigH.

Language: Английский

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