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Abstract
Plasmodium falciparum malaria impacts 100,000+ pregnancies annually, leading to pregnancy loss, preterm delivery, and infant low birth weight attributed to placental malaria (PM). PM is initiated by parasitized erythrocyte binding, precipitating pathogenesis via dysregulated maternal inflammatory and coagulation responses. In Chapter 2, I hypothesized that these pathogenic processes are interconnected and that reducing one pathway will alleviate the other, improving pregnancy outcomes. My approach tests this hypothesis genetically and therapeutically using a mouse model that simulates human PM. Previous work showed that ablation of the inflammatory mediator, tumor necrosis factor (TNF), improves pregnancy outcomes in the mouse model; my work with infected TNF null mutant (TNF-/-) mice corroborates that finding. Transcript analysis of infected TNF-/- mouse embryos reveals reduced expression of a critical molecular link between coagulation and inflammation, protease-activated receptor 2 (F2rl1). Simultaneously, endothelial protein C receptor (Procr) transcripts are elevated, suggesting suppressed coagulation. Prior studies in tissue factor deficient and anticoagulant treated infected wild-type mice showed improved pregnancy outcomes; my studies indicate that anticoagulant treatment may operate by targeting related pathways, since embryonic transcripts for Ifng, Tnf, Il10, Il1b, and Ccl2 are significantly downregulated. Plasma cytokine concentration corroborated the transcript data; IFNγ and IL-10 were significantly decreased by anticoagulant treatment. Antioxidant transcripts such as Nfe2l2 (Nrf2), Sod1, and Sod3 are also considerably reduced, and Procr transcript expression mirrored results obtained in TNF-/- studies. In Chapter 3, I hypothesized that therapeutic targeting of malaria-induced oxidative stress would improve pregnancy outcomes. Deferoxamine treatment, directed at heme/iron-induced oxidative stress, reduced parasitemia and successfully improved pregnancy outcomes. Other treatments directed toward lipid peroxides that promote the cell death modality, ferroptosis, and mitochondrial oxidative stress, were unsuccessful at improving pregnancy outcomes. Finally, Chapter 4 presents recently published work describing a novel murine model of malaria-induced preterm delivery. The research presented in this dissertation advances our understanding of the relationships between two pathogenic responses to PM and describes the limitations of antioxidant therapy in improving pregnancy outcomes in a murine model. These data hold clues that may inform future investigations of therapeutic interventions that can circumvent adverse pregnancy outcomes due to malaria infection.