Repeated malaria exposures associate with skewing of monocytes/macrophages toward a regulatory phenotype

Abstract

Abstract In malaria-naïve individuals, P. falciparum (Pf) infection results in numerous Pf-infected red blood cells (iRBCs) that trigger systemic inflammation and fever. Conversely, repeatedly infected individuals in endemic areas are often asymptomatic and have low levels of iRBCs, even children who have yet to acquire reliably protective antibodies. The molecular mechanisms underlying these clinical observations are unclear. PBMCs collected from Malian children before the malaria season responded to iRBCs by producing pyrogenic, pro-inflammatory mediators such as IL-1β, IL-6 and IL-8. However, following febrile malaria there was a marked shift in the response to iRBCs with the same children’s PBMCs producing lower levels of those cytokines. These data suggest that malaria-induced epigenetic reprogramming of innate immune cells may play a role in immunity to malaria. Accordingly, age-stratified analysis of monocytes collected before the malaria season showed an inverse relationship between age and pro-inflammatory cytokine production capacity. Monocytes of Malian adults expressed higher levels of CD163 and arginase1, associated with a regulatory phenotype. These observations were recapitulated with an in vitro system of monocyte-macrophage differentiation whereby re-exposure to iRBCs was associated with diminished expression of pro-inflammatory mediators and a corresponding decrease in epigenetic markers of active gene transcription (i.e. H3K4me3) at the TSS of the same pro-inflammatory mediators. Together these data support the hypothesis that epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype contributes to clinical immunity to malaria.