A single malaria episode induces mechanisms that minimise inflammation and promote tolerance in spleen inflammatory monocytes.
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ABSTRACT:
PROVIDER: PRJNA630989 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11728800_1.fastq.gz | Fastqsanger.gz | |||
| SRR11728800_2.fastq.gz | Fastqsanger.gz | |||
| SRR11728801_1.fastq.gz | Fastqsanger.gz | |||
| SRR11728801_2.fastq.gz | Fastqsanger.gz | |||
| SRR11728802_1.fastq.gz | Fastqsanger.gz |
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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.
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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 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.
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