Plasmodium falciparummalaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype
Authors: Guha Rajan , Mathioudaki Anna , Doumbo Safiatou , Doumtabe Didier , Skinner Jeff , Arora Gunjan , Siddiqui Shafiuddin , Li Shanping , Kayentao Kassoum , Ongoiba Aissata , Zaugg Judith , Traore Boubacar , Crompton Peter D. 
Published: October 2020

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 repeatedPfinfections over many years, the risk ofPf-iRBC-triggered inflammatory symptoms decreases with cumulativePfexposure. The molecular mechanisms underlying these clinical observations remain unclear. Age-stratified analyses of monocytes collected from uninfected, asymptomatic Malian individuals before the malaria season revealed an inverse relationship between age andPf-iRBC-inducible inflammatory cytokine (IL-1β, IL-6 and TNF) production, whereas Malian infants and malaria-naïve U.S. adults produced similarly high levels of inflammatory cytokines. 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 anin vitrosystem of monocyte to macrophage differentiation wherein macrophages re-exposed toPf-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 thatPfinduces epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype that attenuates inflammatory responses during subsequentPfexposure. These findings also suggest that past malaria exposure could mitigate monocyte-associated immunopathology induced by other pathogens such as SARS-CoV-2.

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 malaria parasites in their blood. 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, too much inflammation can harm infected individuals. In Mali, we conducted a study of a malaria-exposed population from infants to adults and found that participants’ monocytes produced less inflammation as age increases, whereas monocytes of Malian infants and U.S. adults, who had never been exposed to malaria, both produced high levels of inflammatory molecules. Accordingly, monocytes exposed to malaria 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 immune to inflammatory symptoms of malaria and may also help explain why people in malaria-endemic areas appear to be less susceptible to the harmful effects of inflammation caused by other pathogens such as SARS-CoV-2.