A potential for crosstalk between inflammation, coagulation and oxidative stress host responses in malaria induced mid-gestational pregnancy loss in a rodent model

Abstract

Abstract Despite an overall reduction in the global malaria burden, placental malaria (PM) is a major complication of Plasmodium falciparum malaria that impacts hundreds of thousands of pregnancies annually. Primigravid women living in Sub-Saharan Africa are especially prone to PM and often experience poor maternal-fetal health outcomes though pregnancy loss, preterm delivery and infant low birth weight. Mouse models for malaria infection during pregnancy have been instrumental in our current understanding of PM, however our understanding remains incomplete. In the laboratory of Dr. Julie Moore, we have developed a mouse model of infection during pregnancy using the murine-infective species P. chaubaudi chaubaudi AS (PccAS). Infection initiated at gestation day 0 (GD 0) in mice deficient in tumor necrosis factor (TNF) function or signaling and intact C57BL/6J control mice treated with antioxidant and anticoagulant drugs reveals distinct differences in pregnancy outcome at mid-gestation (GD 10). While control mice lose their pregnancies, TNF deficient and drug-treated mice experience rescue of mid-gestational pregnancy and display improved offspring viability at sacrifice. These preliminary findings suggest that by disrupting the function of key host mediators of severe malaria, it may be possible to mitigate negative pregnancy outcomes associated with malaria. Through strategic use of TNF modified mice, combined with studies of gene expression and tissue localization, this work aims to investigate crosstalk between three major host responses to infection - inflammation, coagulation and oxidative stress – and characterize how their interplay may contribute to PM pathogenesis and associated negative pregnancy outcomes.