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| Status |
Public on Nov 26, 2020 |
| Title |
A single malaria episode induces mechanisms that minimise inflammation and promote tolerance in spleen inflammatory monocytes. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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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| Overall design |
Transcriptional response of inflammatory spleen monocytes from C57Bl/6J mice to i) acute (mild P. chaubaudi AS & severe P. chabaudi AJ) and ii) chronic mosquito transmitted P. chabaudi infection. iii) the response of spleen monocytes from chronically malaria infected mice to restimulation with LPS in vitro. iv) their memory response 30 days after drug treatment of chronic P. chabaudi infection. v) spleen inflammatory monocyte response to second infection in our novel reinfection model with identical parasite densities between first and second infection.
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| Contributor(s) |
Nahrendorf W, Ivens AC, Spence PJ |
| Citation(s) |
33752799 |
| Submission date |
May 07, 2020 |
| Last update date |
Mar 29, 2021 |
| Contact name |
Alasdair Ivens |
| E-mail(s) |
al.ivens@ed.ac.uk
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| Phone |
44 131 6513605
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| Organization name |
Centre for Immunity, Infection and Evolution
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| Street address |
Kings Buildings
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| City |
Edinburgh |
| ZIP/Postal code |
EH9 3FL |
| Country |
United Kingdom |
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| Platforms (1) |
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| Samples (53)
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| This SubSeries is part of SuperSeries: |
| GSE150479 |
Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria. |
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| Relations |
| BioProject |
PRJNA630989 |
| SRA |
SRP260457 |
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