Plasmodium Falciparum Malaria Drives Epigenetic Reprogramming Of Human Monocytes Toward A Regulatory Phenotype

In malaria-naive 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-1 beta, IL-6 and TNF) in response to Pf-iRBC stimulation compared to monocytes of Malian children and malaria-naive U.S. adults. Moreover, monocytes of Malian children produced lower levels of IL-1 beta 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.Author summary The malaria parasite is mosquito-transmitted and causes fever and other inflammatory symptoms while circulating in the bloodstream. However, in regions of high malaria transmission the parasite is less likely to cause fever as children age and enter adulthood, even though adults commonly have parasites detected in their blood by microscopy. Monocytes are cells of the innate immune system that secrete molecules that cause fever and inflammation when encountering microorganisms like malaria. Although inflammation is critical to initiating normal immune responses, excessive inflammation can cause disease in infected individuals. In Mali, we conducted a study of a malaria-exposed population from infants to adults and found that monocytes of Malian adults produced less inflammation than monocytes of Malian children and U.S. adults who had never been exposed to malaria. Moreover, monocytes of Malian children tended to produce less inflammation than monocytes of Malian infants. Accordingly, monocytes exposed to malaria parasites in the laboratory became less inflammatory when re-exposed to malaria again later, and these monocytes 'turned down' their inflammatory genes. This study helps us understand how people become resistant to fever and other inflammatory symptoms caused by malaria.