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Exosomal CLOCK-stabilizing lncRNA confers innate memory in tuberculosis resisters [lncRNAseq]

ABSTRACT: Innate immune cells develop enhanced responsiveness to secondary challenges through trained immunity, a process reliant on memory of prior encounters. However, the intercellular regulatory mechanisms and mediators dictating host-protective trained immunity against infections remain incompletely understood. By profiling plasma exosomal long non-coding RNA (lncRNA) repertoires in a tuberculosis (TB) resister cohort resistant to Mycobacterium tuberculosis (Mtb) infection, we identify lncRNA TB Resister-derived CLOCK Regulator 1 (TRCR1) as an immune trainer for monocytes during their differentiation into macrophages. Mechanistically, internalized exosomal TRCR1 collaborates with RNA-binding protein FXR2 to stabilize CLOCK mRNA by forming condensed lncRNA-protein-mRNA complexes in the cytosol, thereby facilitating the expression of CLOCK, a circadian regulator with histone acetyltransferase activity. This upregulated CLOCK amplifies histone H3 acetylation (K9/K14) at promoters of cytokine-encoding and autophagy-related genes, establishing epigenetic memory in monocytes. We further demonstrate that Mtb-secreted antigens induce human lung epithelial cells to release TRCR1-enriched exosomes, which educate monocytes to develop augmented antimicrobial capacity. In mice, TRCR1 training strengthens host anti-Mtb immunity and improves bacille Calmette-Guérin (BCG) vaccine efficacy. Collectively, our findings unveil an intercellular immune training axis wherein exosomal TRCR1 orchestrates CLOCK-mediated epigenetic programming to potentiate innate memory, providing a strategy for refining BCG vaccination and preventing infectious diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285851 | GEO | 2025/11/27

REPOSITORIES: GEO

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Exosomal CLOCK-stabilizing lncRNA confers innate memory in tuberculosis resisters [RNAseq]

Project description:Innate immune cells develop enhanced responsiveness to secondary challenges through trained immunity, a process reliant on memory of prior encounters. However, the intercellular regulatory mechanisms and mediators dictating host-protective trained immunity against infections remain incompletely understood. By profiling plasma exosomal long non-coding RNA (lncRNA) repertoires in a tuberculosis (TB) resister cohort resistant to Mycobacterium tuberculosis (Mtb) infection, we identify lncRNA TB Resister-derived CLOCK Regulator 1 (TRCR1) as an immune trainer for monocytes during their differentiation into macrophages. Mechanistically, internalized exosomal TRCR1 collaborates with RNA-binding protein FXR2 to stabilize CLOCK mRNA by forming condensed lncRNA-protein-mRNA complexes in the cytosol, thereby facilitating the expression of CLOCK, a circadian regulator with histone acetyltransferase activity. This upregulated CLOCK amplifies histone H3 acetylation (K9/K14) at promoters of cytokine-encoding and autophagy-related genes, establishing epigenetic memory in monocytes. We further demonstrate that Mtb-secreted antigens induce human lung epithelial cells to release TRCR1-enriched exosomes, which educate monocytes to develop augmented antimicrobial capacity. In mice, TRCR1 training strengthens host anti-Mtb immunity and improves bacille Calmette-Guérin (BCG) vaccine efficacy. Collectively, our findings unveil an intercellular immune training axis wherein exosomal TRCR1 orchestrates CLOCK-mediated epigenetic programming to potentiate innate memory, providing a strategy for refining BCG vaccination and preventing infectious diseases.

2025-11-27 | GSE285478 | GEO

Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination

Project description:Vaccination against tuberculosis by intradermal Bacillus Calmette-Guérin (BCG) injection saves many lives, supposedly by inducing adaptive immune memory in lymphocytes. Epidemiologically, BCG vaccination is also associated with reduced childhood mortality unrelated to TB, which is attributed to innate immune memory, also termed trained immunity. We recently demonstrated improved protection against tuberculosis infection in highly susceptible rhesus macaques by mucosal BCG vaccination, correlating with a unique local but no peripheral immune profile. Here, we investigated local and peripheral innate immune function after intradermal versus mucosal vaccination with M. bovis BCG or the live attenuated, M. tuberculosis-derived candidate, MTBVAC. The results demonstrate an augmented frequency of trained immunity in monocytes after respiratory mucosal administration of live attenuated mycobacterial vaccines compared to intradermal immunization, with MTBVAC being equally potent as BCG. These results provide further support to strategies for improving TB vaccination and, more broadly, modulating innate immunity via mucosal surfaces.

2021-01-27 | GSE159046 | GEO

Mucosal exposure to non-tuberculous mycobacteria elicits B-cell mediated protection against pulmonary tuberculosis

Project description:Bacille Calmette Guerin (BCG) is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) disease. However, BCG has limited efficacy, necessitating the development of better vaccines. Non-tuberculous mycobacteria (NTM), a distinct lineage from Mtb, are opportunistic pathogens present in the environment. TB endemic countries experience higher exposure to NTM, but previous studies have not elucidated the relationship between NTM exposure and BCG efficacy. Therefore, we developed a mouse model (BCG+NTM) that mimics human BCG vaccination at an early stage and continuous NTM exposure via the oral route, including during TB infection. Our results show that BCG+NTM mice had improved protection against pulmonary TB correlating with increased pulmonary influx of B-cells, higher titers of anti-Mtb IgA and IgG antibodies in serum and airways, compared to mice vaccinated with BCG alone. Notably, the lungs of BCG+NTM mice developed B-cell aggregates expressing markers of germinal center formation as determined by spatial transcriptomics. We conclude a direct correlation between NTM exposure and protection from TB, with B-cells playing a crucial role.

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Lung epithelial signaling mediates early vaccine-induced CD4+ T cell activation and Mtb control

Project description:Tuberculosis (TB) is the leading cause of death due to a single infectious agent. The development of a TB vaccine that induces durable and effective immunity to Mycobacterium tuberculosis (Mtb) infection is urgently needed. Complete and early Mtb control can be induced in M. bovis Bacillus Calmette–Guérin (BCG) vaccinated hosts when the innate immune response is targeted to generate effective vaccine-induced immunity. In the present study, we show that the superior and early Mtb control that is mediated by innate activation of DCs is associated with mucosal localization of clonal activated vaccine-induced CD4+ T cells in the lung. Our studies also show that the lung epithelial cell signaling through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB pathway is critical for the mucosal localization of activated vaccine-induced CD4+ T cells for rapid Mtb control. Thus, our study provides novel insights into the immune mechanisms that can overcome TB vaccine bottlenecks and provide early rapid Mtb control.

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A Ferritin Mutant Induces Protective Immunity against Virulent Mycobacterium tuberculosis Infection

Project description:Iron plays a critical role in the pathogenesis of many organisms including Mtb. It is the preferred redox cofactor in many basic cellular processes but due to its insolubility and potential toxicity under physiological conditions is a limiting nutrient in the host environment. Previously, we demonstrated that Mtb requires the iron storage protein ferritin (BfrB), for adaptation to both low and sufficient concentrations of environmental iron. We also showed that absence of bfrB compromises the ability of Mtb to overcome iron deficiency and prevent excess iron toxicity. In this study, we tested whether vaccination with ?bfrB could elicit host protective immune response against virulent Mtb infection. The results show that immunization of mice with the ?bfrB stimulates protective immunity associated with reduced immunopathology and better containment of the infection compared to vaccination with BCG. Genome-wide transcriptome analysis showed a distinct expression pattern of significantly differentially expressed genes (SDEG) between the ?bfrB and BCG-vaccinated, Mtb-infected mice lungs. Our network/pathway analysis of SDEG revealed significant inhibition of inflammatory response genes and activation of fibrosis genes in the ?bfrB, compared to BCG vaccinated, Mtb-infected mice lungs. The results provide a frame work for the study of mechanisms of protection relevant for the design of new and improved preventive strategies for TB. Female C57BL/6 mice were vaccinated subcutaneously with ?bfrB or BCG . At 8 weeks post-vaccination, mice were aerosol infected with Mtb H37Rv. At 4 weeks post infection, mice were sacrificed and lungs were removed. Lung total RNA from vaccinated and Mtb-infected mice was extracted, purified and were processed separately for microarray analysis.

2014-09-01 | E-GEOD-58810 | biostudies-arrayexpress

Dissecting the immunogenicity of RD1-recombinant live tuberculosis vaccine candidates studying host-pathogen interaction in human primary dendritic cells

Project description:New tuberculosis vaccines are highly desirable and urgently needed since the attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) provides only variable efficacy against the pulmonary form of the disease. The region of difference 1 (RD1), which is deleted in BCG and strongly impacts on Mycobacterium tuberculosis (Mtb) virulence and immunogenicity, represents a crucial locus to be engineered for either the improvement of the current BCG vaccine, or the attenuation of Mtb. Therefore, mutants secreting or not wild-type or mutated variants of the RD1-encoded 6 kDa early secreted antigenic target (ESAT-6) were generated. Comparative analysis of the transcriptome, phenotype, cytokine production profiles and the capacity to promote T cell responses were conducted in human primary dendritic cells (DCs), as they represent critical regulators of vaccine-induced immunity, unveiling a distinct immunogenic potential for BCG or Mtb mutants. In contrast to Mtb, BCG induced a poor DC maturation, and to our surprise, a BCG strain complemented with the RD1 region only partially restored DC maturation and expansion of interferon (IFN)-Î³ producing T cells. In contrast, infection with a recombinant attenuated Mtb strain, secreting a truncated version of ESAT-6 lacking 11 amino acids at the C-terminus portion, drove full maturation in infected DC and maintained their capacity to promote polarization of T helper (Th) 1 cells, as observed upon infection with the virulent Mtb. We performed a comparative microarray analysis of dendritic cells (DCs), infected with Mtb and BCG strains, expressing/complemented (MtbÎRD1::RD1 and BCG::RD1) or not (MtbÎRD1::B412 and BCG::B412) the/with the RD1 region. DCs were challenged with different BCG and Mtb recombinant strains for 8h.

2016-07-03 | E-GEOD-62423 | biostudies-arrayexpress

M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [EG_SERIES_3]

Project description:A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of BCG or b-glucan reprograms HSCs in the BM via a type II interferon (IFN-II) or IL1 response, respectively, that confers protective trained immunity against Mtb. Yet, whether BCG/β-Glucan is unique in its ability to induce this protection remains unknown. Herein, we demonstrate that unlike BCG or b-glucan, Mtb reprograms HSCs via IFN-I response that suppresses myelopoiesis and impairs protective trained immunity to Mtb. Mechanistically, IFN-I response dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death in myeloid progenitors. Finally, activation of IFN-I/iron axis in myeloid progenitors generates a detrimental trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the bone marrow that controls the magnitude and anti-microbial capacity of innate immunity to infection

2020-08-13 | GSE156136 | GEO

M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [AERO_SERIES_2]

2020-08-13 | GSE156135 | GEO

M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [Bulk_SERIES_1]

2020-08-13 | GSE156134 | GEO

A Ferritin Mutant Induces Protective Immunity against Virulent Mycobacterium tuberculosis Infection

Project description:Iron plays a critical role in the pathogenesis of many organisms including Mtb. It is the preferred redox cofactor in many basic cellular processes but due to its insolubility and potential toxicity under physiological conditions is a limiting nutrient in the host environment. Previously, we demonstrated that Mtb requires the iron storage protein ferritin (BfrB), for adaptation to both low and sufficient concentrations of environmental iron. We also showed that absence of bfrB compromises the ability of Mtb to overcome iron deficiency and prevent excess iron toxicity. In this study, we tested whether vaccination with ∆bfrB could elicit host protective immune response against virulent Mtb infection. The results show that immunization of mice with the ∆bfrB stimulates protective immunity associated with reduced immunopathology and better containment of the infection compared to vaccination with BCG. Genome-wide transcriptome analysis showed a distinct expression pattern of significantly differentially expressed genes (SDEG) between the ∆bfrB and BCG-vaccinated, Mtb-infected mice lungs. Our network/pathway analysis of SDEG revealed significant inhibition of inflammatory response genes and activation of fibrosis genes in the ∆bfrB, compared to BCG vaccinated, Mtb-infected mice lungs. The results provide a frame work for the study of mechanisms of protection relevant for the design of new and improved preventive strategies for TB.

2014-09-01 | GSE58810 | GEO

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