Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype.

BioRxiv : the Preprint Server for Biology
Rajan GuhaPeter D Crompton


In malaria-naïve children and adults, Plasmodium falciparum -infected red blood cells ( Pf -iRBCs) trigger fever and other symptoms of systemic inflammation. However, in endemic areas where individuals experience repeated Pf infections over many years, the risk of Pf -iRBC-triggered inflammatory symptoms decreases with cumulative Pf exposure. The molecular mechanisms underlying these clinical observations remain unclear. Age-stratified analyses of monocytes collected from uninfected, asymptomatic Malian individuals before the malaria season revealed an inverse relationship between age and Pf -iRBC-inducible inflammatory cytokine (IL-1β, IL-6 and TNF) production, whereas Malian infants and malaria-naïve U.S. adults produced similarly high levels of inflammatory cytokines. Accordingly, monocytes of Malian adults produced more IL-10 and expressed higher levels of the regulatory molecules CD163, CD206, Arginase-1 and TGM2. These observations were recapitulated in an in vitro system of monocyte to macrophage differentiation wherein macrophages re-exposed to Pf -iRBCs exhibited attenuated inflammatory cytokine responses and a corresponding decrease in the epigenetic marker of active gene transcription, H3K4me3, at inflammatory cytoki...Continue Reading

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flow cytometry

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