Doumtabe, D. | Search bioRxiv

bioRxiv2021

Constant rate of Plasmodium falciparum sexual commitment promotes variable gametocyte proportions as infection progresses over time

Plasmodium falciparum infections persist through long dry seasons at low parasitaemia without causing malaria symptoms and thus remain untreated. In asymptomatic children, increased circulation of infected erythrocytes without adhering to the vascular endothelium is observed during the dry months, compared to febrile malaria in the wet season. However, alterations of parasite sexual commitment and gametocytogenesis have not been investigated. Here, we compared the expression of genes related to sexual commitment and gametocytogenesis, the proportion and density of P. falciparum gametocytes, and the blood concentration of phospholipids in dry season asymptomatic individuals versus symptomatic subjects in the wet season. Additionally, we adapted a within-host mathematical model considering asexual and sexually-committed parasites and gametocytes to understand the dynamics of gametocyte number and proportion as infections progress. Compared to clinical malaria cases, transcripts of late-stage gametocytes were predominantly upregulated in the dry season, associating with increased proportions of mature gametocytes; while transcription of genes related to parasite sexual commitment was unaltered throughout the year. Our data suggest that gametocyte density and proportion diverge as infections progress from recent transmission to chronic carriage, without alterations in the sexual commitment rate over time.

microbiology↗

bioRxiv2020

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 monocytes collected from uninfected, asymptomatic Malian individuals before the malaria season revealed an inverse relationship between age and Pf-iRBC-inducible inflammatory cytokine (IL-1{beta}, IL-6 and TNF) production, whereas Malian infants and malaria-naive 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 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. These findings also suggest that past malaria exposure could mitigate monocyte-associated immunopathology induced by other pathogens such as SARS-CoV-2. Author SummaryThe 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.

immunology↗