BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA422382 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6376040_1.fastq.gz | Fastqsanger.gz | |||
| SRR6376040_2.fastq.gz | Fastqsanger.gz | |||
| SRR6376041_1.fastq.gz | Fastqsanger.gz | |||
| SRR6376041_2.fastq.gz | Fastqsanger.gz | |||
| SRR6376042_1.fastq.gz | Fastqsanger.gz |
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Project description:The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remains unknown. Here we show that access of Bacillus Calmette-Guérin (BCG) to the bone marrow (BM) changes the transcriptional landscape of hematopoietic stem cells (HSC) and multipotent progenitors (MPP) leading to local cell expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, BCG-educated HSCs generate epigenetically-modified macrophages that provide significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCG-induced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.
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Project description:BCG reprogramming of hematopoietic stem cells generates protective innate immunity against tuberculosis
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Project description:The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remains unknown. Here we show that access of Bacillus CalmetteGuérin (BCG) to the bone marrow (BM) following intravenous immunization induced local hematopoietic stem cell (HSC) expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, HSC reprogramming led to the generation of epigeneticallymodified macrophages that provided significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCGinduced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.
2017-12-13 | GSE98599 | GEO
Project description:The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remains unknown. Here we show that access of Bacillus CalmetteGuérin (BCG) to the bone marrow (BM) following intravenous immunization induced local hematopoietic stem cell (HSC) expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, HSC reprogramming led to the generation of epigeneticallymodified macrophages that provided significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCGinduced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.
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Project description:The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remains unknown. Here we show that access of Bacillus CalmetteGuérin (BCG) to the bone marrow (BM) following intravenous immunization induced local hematopoietic stem cell (HSC) expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, HSC reprogramming led to the generation of epigeneticallymodified macrophages that provided significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCGinduced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.
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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.
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Project description:Bacillus Calmette-Guérin (BCG) vaccine is one of the most widely-used vaccines worldwide. In addition to protection against tuberculosis, BCG confers a degree of non-specific protection against other infections by enhancing secondary immune responses to heterologous pathogens, an effect termed trained immunity. To better understand BCG-induced immune reprogramming, we performed single-cell transcriptomic measurements before and after BCG vaccination using secondary immune stimulation with bacterial lipopolysaccharide (LPS). We find that BCG vaccination reduces systemic inflammation, and we identify 75 genes with an altered response to LPS, including several inflammatory mediators such as CCL3 and CCL4 which have a heightened response. Co-expression analysis reveals gene modules containing these cytokines lose coordination after BCG vaccination. Others have increased coordination, including several humanin nuclear isoforms which we confirmed induce trained immunity in vitro. Our results link in vivo BCG administration to single cell transcriptomic changes, validated in human genetics experiments, and highlight new genes which may be responsible for the non-specific protective effects of BCG.
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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.
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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.
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