Open AccessPlasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype
Author(s) -
Rajan Guha,
Anna Mathioudaki,
Safiatou Doumbo,
Didier Doumtabé,
Jeff Skinner,
Gunjan Arora,
Shafiuddin Siddiqui,
Shanping Li,
Kassoum Kayentao,
Aïssata Ongoïba,
Judith B. Zaugg,
Boubacar Traoré,
Peter D. Crompton
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009430
Subject(s) - immunology , biology , plasmodium falciparum , malaria , monocyte , epigenetics , reprogramming , cd163 , cytokine , inflammation , interleukin 10 , macrophage , in vitro , gene , genetics
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 uninfected, asymptomatic Malian individuals before the malaria season revealed that monocytes of adults produced lower levels of inflammatory cytokines (IL-1β, IL-6 and TNF) in response to Pf -iRBC stimulation compared to monocytes of Malian children and malaria-naïve U.S. adults. Moreover, monocytes of Malian children produced lower levels of IL-1β and IL-6 following Pf -iRBC stimulation compared to 4–6-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 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 cytokine gene loci. Together these data indicate that Pf induces epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype that attenuates inflammatory responses during subsequent Pf exposure. Trial Registration : ClinicalTrials.gov NCT01322581 .