A single malaria episode induces mechanisms that minimise inflammation and promote tolerance in spleen inflammatory monocytes.
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PROVIDER: PRJNA630989 | ENA |
REPOSITORIES: ENA
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Project description:Disease tolerance is an important alternative strategy for rapidly acquired immunity to malaria. We show that tolerance is induced by a single malaria episode - in the absence of parasite clearance. Inflammatory spleen monocytes from C57Bl6/J mice respond with interferon-stimulated inflammation to acute first Plasmodium chabaudi infection and are destined to differentiate into inflammatory macrophages. This dramatic transcriptional response is tolerised during persisting chronic infection (with parasite densities up to 1000 parasites per µl), since the fitness costs of maintaining an emergency inflammatory response for several months would not be compatible with survival. However, spleen monocytes from chronically infected mice are not in a permanent refractory state, since their inflammatory response is identical to monocytes from uninfected mice when removed from the spleen and stimulated with LPS in vitro. Using a newly developed reinfection model to closely match parasitaemia between first and second P. chabaudi infection, we further uncover that memory of first malaria infection (30 days after drug treatment of chronic infection) dramatically changes the transcriptional response of inflammatory spleen monocytes to second infection. They now minimise inflammation and instead promote stress and tissue tolerance. This unique functional profile is not underpinned by alterations in the epigenetic landscape of inflammatory monocytes before their release from the bone marrow (link to GEO ChIPseq) - tolerance is therefore imprinted within the spleen. Hosts thus acquire long-lasting mechanisms that control inflammation (reducing collateral tissue damage) and learn to actively promote stress tolerance (protecting tissues against toxic products and processes) after one malaria episode.
2020-11-26 | GSE150047 | GEO
Project description:Disease tolerance is an important alternative strategy for rapidly acquired immunity to malaria. We show that tolerance is induced by a single malaria episode - in the absence of parasite clearance. Inflammatory spleen monocytes from C57Bl6/J mice with memory of malaria infection dramatically change their transcriptional response to a second infection; instead of driving emergency inflammation they promote stress and tissue tolerance (RNAseq data available in GEO series GSE150047). This unique functional profile is not underpinned by alterations in the epigenetic landscape of inflammatory monocytes before their release from the bone marrow (ChIPseq data available in GEO series GSE150478) - tolerance is therefore imprinted within the spleen (microarray data available in GEO series GSE149894). Hosts thus acquire long-lasting mechanisms that control inflammation (reducing collateral tissue damage) and learn to actively promote stress tolerance (protecting tissues against toxic products and processes) after one malaria episode.
2020-11-26 | GSE150479 | GEO
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:Dendritic cells have an important role in immune surveillance. After being exposed to microbial components, they migrate to secondary lymphoid organs and activate T lymphocytes. During mouse model malaria, splenic inflammatory monocytes differentiate into monocyte-derived dendritic cells (MO-DCs), which are CD11b+F4/80+CD11c+MHCIIhighDC-SIGNhighLy6c+ and express high levels of CCR5, CXCL9 and CXCL10 (CCR5+CXCL9/10+ MO-DCs). We intend to use these malaria-induced splenic MO-DCs gene expression data to understand more about the migratory route taken by these cells as well the most important genes/pathways involved on this cell differentiation in the spleen, allowing them to migrate to the brain where they develop an important role in cerebral malaria.
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Project description:Blood-stage malaria initiates both innate and adaptive immune responses, inclusive a strong activation of the mononuclear phagocyte network. Here we show that Plasmodium infection results in a transient loss of embryonically established tissue-resident macrophages in spleen, liver and lungs, much before the peak of parasitemia. During acute blood-stage malaria, fate mapping analysis revealed that inflammatory monocytes contribute to the repopulation of the emptied niches of splenic red pulp macrophages and hepatic Kupffer cells, while lung alveolar macrophages refill their niche mainly through self-renewal. Interestingly, the local microenvironment of spleen and liver can “imprint” the molecular characteristics of fetal-derived macrophages in new immigrants from bone marrow including almost identical gene expression profiles and turnover kinetics.
2018-12-11 | GSE115906 | GEO
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Project description:Spleen tyrosine kinase (Syk)del/del mice suppressed atherosclerosis and Sykdeldel macrophages showed cell migration impairment. To investigate the Syk-associated genes in cell migration, we analyzed RNA-Seq of bone marrow monocytes.
2023-07-20 | GSE205972 | GEO
Project description:Chronic inflammation during placental malaria (PM) caused by Plasmodium falciparum is most frequent in first-time mothers and is associated with poor maternal and fetal outcomes. In the first genome wide analysis of the local human response to sequestered malaria parasites, we identified genes associated with chronic PM, then localized the corresponding proteins and immune cell subsets in placental cryosections. Experiment Overall Design: Placental samples from twenty first-time mothers were selected based on placental malaria (PM) status and RNA quality. Ten had active PM-episodes, seven of which had inflammatory cells on histology. Of the ten PM-negative women, five had histological evidence of a past PM-episode, including one with inflammatory cells.
2008-06-15 | E-GEOD-7586 | biostudies-arrayexpress
Project description:To understand the functional relationship between brain dendritic cells (brain DCs) and other myeloid cells, we compared the gene expression profile of m/chDCs to that of bone marrow monocytes, brain microglia and classical spleen CD8+ and CD8- DCs. In order to obtain enough brain DCs for mRNA extraction, we expanded brain DCs with in vivo Flt3L treatment before purification. This study includes data from FACs Aria-purified brain DCs, bone marrow monocytes, brain microglia and classical spleen CD8+ and CD8- DCs. The genearray was performed to compare expression of cell surface endocytic receptor, cytokine receptors, TLRs, transcription factors, molecules for antigen processing and presentation. Each Series consists of 3 individuall samples
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Project description:Monocytes are immune cells which differentiate into subsets through sequential transition. The life-time differs between the individual subsets ranging from 1 day to 1 week. We studied the involvement of IL-4 receptor signaling on monocyte survival in mice lacking IL-4 receptors in a total knockout and a myeloid knockout. Circulating leukocytes were reduced by 25% in both knockouts, which was mainly caused by a 50% reduction of monocytes. Using RNA sequencing we were able to demonstrate that spleen monocytes in IL-4Rα deficient mice express lower amounts of anti-apoptotic genes and increased amounts of cell adhesion molecules hinting to an increase in apoptotic potential of these cells. This data were also verified in spleen samples were we found an increase of apoptotic monocytes identified by TUNEL and cleaved caspase 3 staining. Mechanistically we were able to show that IL-4 signaling directly affects the lifespan of monocytes in vivo. Therefore, we identified a previously unknown function of basal IL-4 levels in homeostasis of monocytes by regulating the lifespan and preventing apoptosis of the cells.
2022-09-01 | GSE168143 | GEO