Molecular and cellular underpinnings of placental malaria - PROJECT SUMMARY/ABSTRACT Malaria in pregnancy poses significant threat to the wellbeing of the mother, fetus, and neonate and in sub- Saharan Africa, it kills 100,000 infants annually and accounts for about 20% of stillbirths. These fetal adverse outcomes are mainly due to the sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous spaces, resulting in placental malaria (PM). This happens even when malaria infection is asymptomatic and undetectable in maternal blood. The burden of PM is worsened by rising resistance to intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP), which is recommended for malaria chemoprophylaxis during pregnancy. Indeed, our data show that many women on IPTp-SP who test malaria negative and are asymptomatic, still have PM. PM is associated with several adverse effects on the fetus, including fetal growth restriction, preterm birth, and neonatal morbidity and mortality. The adverse outcomes are mainly due to placental injury and not fetal infection by Plasmodium falciparum, which is rare. Since the placenta is inaccessible during pregnancy, the impact of PM on placental biology is unclear, and there are no tools for PM detection during pregnancy, representing a critical research gap. These factors and the limited understanding of the effects of PM on placental function and physiology significantly hamper the development of effective PM interventions and diagnostic tools. However, the placenta sheds vast amounts of extracellular vesicles into maternal circulation, offering a non-invasive readout of the fetal environment. To comprehensively understand the cellular and molecular processes that underlie PM-driven placental pathobiology, we propose to leverage our well-defined placental biobank to, 1) identify the transcriptomic signatures of PM-induced placental pathobiology, and 2) identify PM-associated transcriptomic signatures in maternal circulation. The latter will be implemented by profiling the transcriptome of maternally circulating placental extracellular vesicles and by identifying placenta-originated cell-free RNA in maternal circulation. These analyses will uncover processes/factors underlying PM-induced placental pathobiology and those that can be targeted to prevent or mitigate PM. The identified PM biomarkers will be leveraged to develop effective point-of-care tools for PM diagnosis in low-resource settings, which have the potential to significantly improve maternal and child health outcomes. The proposed work will also build a strong foundation in research networks, infrastructure, skills, and data for follow up studies on the pathobiology of PM and its consequences for the developing child. Moreover, the strategies, experience, knowledge, tools, and platforms used in this study can be extended to other common placental infections in sub-Saharan Africa.
