Immunopathogenesis of Severe Malaria During Pregnancy

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DESCRIPTION (provided by applicant): Every year, more than 200 million people suffer from malarial infection worldwide, leading to nearly 1 million deaths. Infection during pregnancy and early childhood accounts for the majority of malarial morbidity and mortality. Poor birth outcomes induced by maternal Plasmodium falciparum infection range from pre-term delivery and intrauterine growth restriction to abortion and stillbirth. These poor birth outcomes have been linked to a number of malaria-induced placental pathologies, including maternal inflammatory infiltrate and excessive fibrin deposition in the maternal blood space, but the underlying etiology has not been described. The murine model that we have developed, which utilizes P. chabaudi infection in C57BL/6 and A/J mice, shows great promise for identifying the mechanistic basis for malaria-associated compromise of pregnancy., The objective of this application is to use this model system to identify the molecular mechanisms that drive inflammation and hypercoagulation in maternal malaria, leading to poor birth outcomes. The central hypothesis for the proposed research is that systemic and placental malaria-induced inflammatory responses mediate pregnancy loss via dysregulated coagulation or placental cellular inflammatory infiltrate, depending on both maternal and fetal contributions. The objectives of the proposal will be achieved through two Specific Aims. In the first Aim, the role o Tissue Factor in malaria-induced embryonic loss will be characterized. Using a variety of genetically manipulated mice and pharmacological manipulation of coagulation, the importance of Tissue Factor in driving coagulation, inflammatory responses, placental damage and embryo loss will be assessed. The role of Protease Activated Receptors, which are activated by products of the coagulation cascade, including Tissue Factor, will also be evaluated. In the second Aim, the molecular basis for differential placental pathological outcomes of malaria-infected B6 and A/J mice will be explored. Using genetically manipulated mice and pharmacological manipulation of oxidative stress, the cells, soluble factors and processes responsible for placental damage in these strains will be evaluated, with molecular evidence of placental apoptosis representing placental damage and embryo compromise. Successful completion of this work promises to reveal to an unprecedented extent the mechanistic basis for malaria-associated fetal compromise and could pave the way for new treatment modalities for malaria-exposed pregnant women. Progress on this front is critical given the lack of a protective malaria vaccine and the perpetual emergence of parasite resistance to frontline anti-malarial drugs. New interventions for malaria during pregnancy could contribute to significant reduction in the morbidity and fetal compromise associated with this disease.