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BACKGROUND: Plasmodium falciparum causes placental malaria, which results in adverse outcomes for mother and child. P. falciparum-infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease. The objective of this study was to develop a prediction model using antibody features that could identify women protected from placental malaria. METHODS: We used a systems serology approach with elastic net-regularized logistic regression, partial least squares discriminant analysis, and a case-control study design to identify naturally acquired antibody features mid-pregnancy that were associated with protection from placental malaria at delivery in a cohort of 77 pregnant women from Madang, Papua New Guinea. RESULTS: The machine learning techniques selected 6 out of 169 measured antibody features towards VAR2CSA that could predict (with 86% accuracy) whether a woman would subsequently have active placental malaria infection at delivery. Selected features included previously described associations with inhibition of placental binding and/or opsonic phagocytosis of infected erythrocytes, and network analysis indicated that there are not one but multiple pathways to protection from placental malaria. CONCLUSIONS: We have identified candidate antibody features that could accurately identify malaria-infected women as protected from placental infection. It is likely that there are multiple pathways to protection against placental malaria. FUNDING: This study was supported by the National Health and Medical Research Council (Nos. APP1143946, GNT1145303, APP1092789, APP1140509, and APP1104975).

Background: Plasmodium falciparum causes placental malaria, which results in adverse outcomes for mother and child. P. falciparum-infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease. The objective of this study was to develop a prediction model using antibody features that could identify women protected from placental malaria.Methods: We used a systems serology approach with elastic net-regularized logistic regression, partial least squares discriminant analysis, and a case-control study design to identify naturally acquired antibody features mid-pregnancy that were associated with protection from placental malaria at delivery in a cohort of 77 pregnant women from Madang, Papua New Guinea.Results: The machine learning techniques selected 6 out of 169 measured antibody features towards VAR2CSA that could predict (with 86% accuracy) whether a woman would subsequently have active placental malaria infection at delivery. Selected features included previously described associations with inhibition of placental binding and/or opsonic phagocytosis of infected erythrocytes, and network analysis indicated that there are not one but multiple pathways to protection from placental malaria.Conclusions: We have identified candidate antibody features that could accurately identify malaria-infected women as protected from placental infection. It is likely that there are multiple pathways to protection against placental malaria.Funding: This study was supported by the National Health and Medical Research Council (Nos. APP1143946, GNT1145303, APP1092789, APP1140509, and APP1104975).

While half of the world's population is at risk of malaria, the most vulnerable are still children under five, pregnant women and returning travelers. Anopheles mosquitoes transmit malaria parasites to the human host; but how Plasmodium interact with the innate immune system remains largely unexplored. The most recent advances prove that monocytes are a key component to control parasite burden and to protect host from disease. Monocytes' protective roles include phagocytosis, cytokine production and antigen presentation. However, monocytes can be involved in pathogenesis and drive inflammation and sequestration of infected red blood cells in organs such as the brain, placenta or lungs by secreting cytokines that upregulate expression of endothelial adhesion receptors. Plasmodium DNA, hemozoin or extracellular vesicles can impair the function of monocytes. With time, reinfections with Plasmodium change the relative proportion of monocyte subsets and their physical properties. These changes relate to clinical outcomes and might constitute informative biomarkers of immunity. More importantly, at the molecular level, transcriptional, metabolic or epigenetic changes can "prime" monocytes to alter their responses in future encounters with Plasmodium. This mechanism, known as trained immunity, challenges the traditional view of monocytes as a component of the immune system that lacks memory. Overall, this rough guide serves as an update reviewing the advances made during the past 5 years on understanding the role of monocytes in innate immunity to malaria.