Applying Interdisciplinary Approaches in Defining Molecular Pathways in Placental Malaria (360G-Wellcome-322224_Z_24_Z)

Placental malaria (PM), caused by Plasmodium falciparum sequestration via VAR2CSA, significantly contributes to maternal and neonatal morbidity in sub- Saharan Africa. The mechanisms underlying PM's diverse outcomes—from normal deliveries to severe complications—remain unclear. This research aims to elucidate these mechanisms using advanced multi-omics technologies, computational analyses, and functional studies. We will investigate the genetic and epigenetic diversity of P. falciparum isolates, focusing on variable regions like var genes, to identify parasite variants linked to adverse outcomes. Utilizing single-cell RNA sequencing, spatial transcriptomics, and proteomics, we will map disrupted molecular pathways in PM-infected placental tissues, revealing key factors in placental dysfunction. An integrative systems biology framework with machine learning will construct a maternal–fetal–parasite interactome, enabling predictive models for PM outcomes and identifying intervention points. Functional validation using CRISPR-Cas9 gene editing in trophoblast cell lines and organoids will confirm roles of identified genes. This interdisciplinary research will advance understanding of PM pathogenesis, uncover diagnostic biomarkers and therapeutic targets, and establish a regional center of excellence for placental health research in Eastern Africa. Key words: placental malaria, Plasmodium falciparum, multi-omics, genomics, transcriptomics, proteomics, epigenetics, maternal–fetal interaction, machine learning, systems biology, VAR2CSA, adverse pregnancy outcomes.