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However, in endemic areas where individuals experience repeated\n                    <jats:italic>Pf<\/jats:italic>\n                    infections over many years, the risk of\n                    <jats:italic>Pf<\/jats:italic>\n                    -iRBC-triggered inflammatory symptoms decreases with cumulative\n                    <jats:italic>Pf<\/jats:italic>\n                    exposure. The molecular mechanisms underlying these clinical observations remain unclear. Age-stratified analyses of uninfected, asymptomatic Malian individuals before the malaria season revealed that monocytes of adults produced lower levels of inflammatory cytokines (IL-1\u03b2, IL-6 and TNF) in response to\n                    <jats:italic>Pf<\/jats:italic>\n                    -iRBC stimulation compared to monocytes of Malian children and malaria-na\u00efve U.S. adults. Moreover, monocytes of Malian children produced lower levels of IL-1\u03b2 and IL-6 following\n                    <jats:italic>Pf<\/jats:italic>\n                    -iRBC stimulation compared to 4\u20136-month-old infants. 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\n                    <jats:italic>in vitro<\/jats:italic>\n                    system of monocyte to macrophage differentiation wherein macrophages re-exposed to\n                    <jats:italic>Pf<\/jats:italic>\n                    -iRBCs exhibited attenuated inflammatory cytokine responses and a corresponding decrease in the epigenetic marker of active gene transcription, H3K4me3, at inflammatory cytokine gene loci. Together these data indicate that\n                    <jats:italic>Pf<\/jats:italic>\n                    induces epigenetic reprogramming of monocytes\/macrophages toward a regulatory phenotype that attenuates inflammatory responses during subsequent\n                    <jats:italic>Pf<\/jats:italic>\n                    exposure.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration<\/jats:bold>\n                    : ClinicalTrials.gov\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01322581?term=NCT01322581&amp;draw=2&amp;rank=1\" xlink:type=\"simple\">NCT01322581<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009430","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T13:22:50Z","timestamp":1617715370000},"page":"e1009430","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":77,"title":["Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory 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