Malaria pigment hemozoin-induced transcriptional remodeling of mouse hematopoietic stem and progenitor cells, granulocyte-macrophage progenitors, and bone marrow monocytes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA929995 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23291031_1.fastq.gz | Fastqsanger.gz | |||
| SRR23291031_2.fastq.gz | Fastqsanger.gz | |||
| SRR23291032_1.fastq.gz | Fastqsanger.gz | |||
| SRR23291032_2.fastq.gz | Fastqsanger.gz | |||
| SRR23291033_1.fastq.gz | Fastqsanger.gz |
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Project description:Malaria pigment hemozoin-induced chromatin remodeling of mouse hematopoietic stem and progenitor cells, granulocyte-macrophage progenitors, and bone marrow monocytes
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Project description:Trained immunity is the phenomenon whereby innate immune cells such as monocytes or macrophages, and their progenitors in the bone-marrow, undergo functional reprogramming after exposure to certain microbial and danger signals, altering their responses to future exposures. In this study, we performed a non-lethal Plasmodium yoelii 17XNL (Py) infection in wild-type C57/BL6J mice to investigate the underlying mechanism of Py-induced myelopoiesis and performed transcriptomic analysis on HSPCs, GMPs, and monocytes 6 weeks following exposure. Next cecal ligation and puncture (CLP) was used to model sepsis in vivo as a secondary exposure, and the transcriptomes of PBS and Py-exposed monocytes were generated.
2025-01-08 | GSE224161 | GEO
Project description:Trained immunity is the phenomenon whereby innate immune cells such as monocytes or macrophages, and their progenitors in the bone-marrow, undergo functional reprogramming after exposure to certain microbial and danger signals, altering their responses to future exposures. In this study, we performed a non-lethal Plasmodium yoelii 17XNL (Py) infection in wild-type C57/BL6J mice to investigate the underlying mechanism of Py-induced myelopoiesis and performed chromatin accessibility analysis on HSPCs, GMPs, and monocytes 6 weeks following exposure.
2025-01-08 | GSE224160 | GEO
Project description:Severe presentations of malaria, arising from Plasmodium spp. infection, are often associated with accumulation of circulating bilirubin, a condition known as hyperbilirubinemia or jaundice of malaria. Whether this represents an adaptive or maladaptive response to Plasmodium spp. infection is not understood. Departing from the textbook view of hyperbilirubinemia reflecting a failure to excrete bilirubin, we demonstrate that bilirubin production by biliverdin reductase A (BLVRA) partakes in a host adaptive response to malaria. Genetic Blvra deletion exacerbated malaria mortality in mice; This was associated with a >10-fold increase in parasite burden, compared to control mice expressing BLVRA, which cleared the parasite and survived malaria. At concentrations in the range of jaundice of malaria, unconjugated bilirubin arrested the proliferation and killed asexual blood stages of the human-infective P. falciparum in vitro. This was associated with disruption of the parasite’s mitochondrion and food vacuole as well as with the accumulation of hemozoin in the parasite’s cytoplasm. Moreover, bilirubin inhibited hemozoin (β-hematin) synthesis in vitro, a vital heme-detoxifying pathway targeted by Quinoline-based antimalarial drugs such as chloroquine. In conclusion, hyperbilirubinemia represents an evolutionary conserved metabolite-based resistance mechanism against malaria.
2025-03-24 | GSE254821 | GEO
Project description:The role of infection in erythropoietic dysfunction is poorly understood. In children with P. falciparum malaria, the by-product of hemoglobin digestion in infected red cells (hemozoin) is associated with the severity of anemia which is independent of circulating levels of the inflammatory cytokine tumor necrosis alpha (TNF-alpha). To gain insight into the common and specific effects of TNF-alpha and hemozoin on erythropoiesis, we studied the gene expression profile of purified primary erythroid cultures exposed to either TNF-alpha (10ng/ml) or to hemozoin (12.5microgram/ml heme units) for 24 hours. Perturbed gene function was assessed using co-annotation of associated gene ontologies and expression of selected genes representative of the profile observed was confirmed by real time PCR (rtPCR). The changes in gene expression induced by each agent were largely distinct; many of the genes significantly modulated by TNF-alpha were not affected by hemozoin. The genes modulated by TNF-alpha were significantly enriched for those encoding proteins involved in the control of type 1 interferon signalling and the immune response to viral infection. In contrast, genes induced by hemozoin were significantly enriched for functional roles in regulation of transcription and apoptosis. Further analyses by rtPCR revealed that hemozoin increases expression of transcription factors that form part of the integrated stress response which is accompanied by reduced expression of genes involved in DNA repair. This study confirms that hemozoin induces cellular stress on erythroblasts that is additional to and distinct from responses to inflammatory cytokines and identifies new genes that may be involved in the pathogenesis of severe malarial anemia. More generally the respective transcription profiles highlight the varied mechanisms through which erythropoiesis may be disrupted during infectious disease. Erythroblasts derived from PBMCs were enriched to 97% purity for proerythroblast and intermediate/normoblast phases of differentiation using magnetic bead isolation. There were three treatment groups: media, P.falciparum hemozoin (12.5 microgram /ml hematin units) and tumour necrosis factor alpha(10ng/ml). Total RNA using 7.5 x105 cells per treatment from one donor was extracted using Trizol. Highly significant gene ontological findings (where p> x10^-17 but < x10^-7) were confirmed by quantitative PCR.
2015-02-04 | E-GEOD-65577 | biostudies-arrayexpress
Project description:Disease tolerance is an alternative strategy for acquired immunity to malaria and can be rapidly induced after a single malaria episode - in the absence of improved parasite clearance. Memory of a first malaria episode dampens the inflammatory profile of spleen monocytes and induces mechanisms of stress tolerance to minimise tissue damage. This begs the question how monocytes are instructed to respond in a different way to second compared to first malaria infection. We asked if malaria alters the epigenetic landscape of inflammatory monocytes before their release from the bone marrow - thus testing the compelling innate memory hypothesis. We compared the genome-wide distribution of histone modifications on flow-sorted bone marrow monocytes from mice with memory of severe mosquito transmitted P. chabaudi AJ infection (30 days after drug cure) and drug treated uninfected age-matched controls using ChIPseq. Specifically, we tested whether once-infected mice have long-lived modifications in i) transcription start sites marked with H3K27ac to activate transcription ii) enhancers or superenhancers marked with H3K4me1 to promote gene expression and iii) in H3K9me3 to condense DNA into heterochromatin thereby silencing gene expression. We found no meaningful differences in the histone modification profiles of 2848 genes that define monocyte function in first and second malaria infection using the motif discovery software HOMER. Furthermore, when calling differentially modified regions (DMR) between once-infected mice and uninfected mice to ask whether there were any measurable differences in the epigenetic landscapes of these genes, we found 95% had no detectable modifications. In those rare cases where a DMR was called, HOMER assigned a low peak score, indicating low confidence and minimal biological relevance. Epigenetic reprogramming does therefore not underpin the functional specialisation of inflammatory monocytes in tolerised hosts. Innate memory is thus not induced by malaria infection in vivo. Instead, altered monocyte function and fate are imprinted within the spleen (link to GEO microarray) to promote disease tolerance.
2020-11-26 | GSE150478 | GEO
Project description:The role of infection in erythropoietic dysfunction is poorly understood. In children with P. falciparum malaria, the by-product of hemoglobin digestion in infected red cells (hemozoin) is associated with the severity of anemia which is independent of circulating levels of the inflammatory cytokine tumor necrosis alpha (TNF-alpha). To gain insight into the common and specific effects of TNF-alpha and hemozoin on erythropoiesis, we studied the gene expression profile of purified primary erythroid cultures exposed to either TNF-alpha (10ng/ml) or to hemozoin (12.5microgram/ml heme units) for 24 hours. Perturbed gene function was assessed using co-annotation of associated gene ontologies and expression of selected genes representative of the profile observed was confirmed by real time PCR (rtPCR). The changes in gene expression induced by each agent were largely distinct; many of the genes significantly modulated by TNF-alpha were not affected by hemozoin. The genes modulated by TNF-alpha were significantly enriched for those encoding proteins involved in the control of type 1 interferon signalling and the immune response to viral infection. In contrast, genes induced by hemozoin were significantly enriched for functional roles in regulation of transcription and apoptosis. Further analyses by rtPCR revealed that hemozoin increases expression of transcription factors that form part of the integrated stress response which is accompanied by reduced expression of genes involved in DNA repair. This study confirms that hemozoin induces cellular stress on erythroblasts that is additional to and distinct from responses to inflammatory cytokines and identifies new genes that may be involved in the pathogenesis of severe malarial anemia. More generally the respective transcription profiles highlight the varied mechanisms through which erythropoiesis may be disrupted during infectious disease.
2015-02-04 | GSE65577 | GEO
Project description:Extracellular vesicle labeled Granulocyte macrophage progenitors
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Project description:Granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) produce monocytes during homeostasis and in response to increased demand during infection. Both progenitor populations are thought to derive from common myeloid progenitors (CMPs), and a hierarchical relationship (CMP-GMP-MDP-monocyte) is presumed to underlie monocyte differentiation. Here, however, we demonstrate that mouse MDPs arose from CMPs independently of GMPs, and that GMPs and MDPs produced monocytes via similar but distinct monocyte-committed progenitors. GMPs and MDPs yielded classical (Ly6Chi) monocytes with gene expression signatures that were defined by their origins and impacted their function. GMPs produced a subset of "neutrophil-like" monocytes, whereas MDPs gave rise to a subset of monocytes that yielded monocyte-derived dendritic cells. GMPs and MDPs were also independently mobilized to produce specific combinations of myeloid cell types following the injection of microbial components. Thus, the balance of GMP and MDP differentiation shapes the myeloid cell repertoire during homeostasis and following infection.
| S-EPMC5726802 | biostudies-literature