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

PLoS Pathog. 2021 Apr 6;17(4):e1009430. doi: 10.1371/journal.ppat.1009430. eCollection 2021 Apr.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • Cytokines / metabolism
  • Erythrocytes / metabolism
  • Humans
  • Infant
  • Inflammation / immunology
  • Inflammation / metabolism
  • Macrophages / metabolism
  • Malaria / blood
  • Malaria / immunology*
  • Malaria, Falciparum / blood
  • Malaria, Falciparum / immunology*
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Phenotype*
  • Plasmodium falciparum / immunology
  • Plasmodium falciparum / metabolism

Substances

  • Cytokines

Associated data

  • ClinicalTrials.gov/NCT01322581

Grant support

This study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, with intramural grants to PDC. RG received Visiting postdoctoral fellowship from National Institute of Allergy and Infectious Diseases, National Institutes of Health. AM, JZ received European Molecular Biology Laboratory (EMBL) Core funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.