Relationships between inflammation, coagulation, and oxidative stress in malaria-induced pregnancy compromise

Abstract

Abstract Plasmodium falciparum malaria in pregnancy contributes to poor birth outcomes in association with placental malaria (PM), a syndrome initiated by parasitized erythrocyte binding, precipitating placental oxidative stress, dysregulated inflammation, and coagulation. We have tested the hypothesis that these pathogenic processes are synergistic in PM using C57BL/6J (B6) mice infected with P. chabaudi. Ablation of tumor necrosis factor (Tnf), anticoagulant treatment, and infection in Tnf−/− and tissue factor-deficient (F3flox/floxTie-2Cre) mice improves pregnancy outcomes. Relative to infected B6 controls, infected Tnf−/− mouse embryos show two to four-fold reduced transcript expression of a key molecular link between coagulation and inflammation, protease activated receptor 2 (F2rl1). Tissue factor (F3) expression is 50% reduced, while endothelial protein C receptor (Procr) transcripts are increased three to five-fold, supporting the bidirectional nature of coagulation and inflammation in PM. Moreover, embryonic transcripts for markers of inflammation (Ifng, Tnf, Il-10, Il-1β, and Ccl2), antioxidants (Sod1, Sod2, and Nfe2l2) and F3 are significantly downregulated in anticoagulant-relative to sham-treated, infected B6 mice, whereas Procr transcripts are elevated, suggesting functionally linkages of the three pathways. Ongoing antioxidant therapeutic studies are expected to confirm perturbations of inflammation and coagulation responses. In sum, this work is contributing to understanding of molecular interactions between the major pathogenic responses to PM, how synergy thereto galvanizes pregnancy compromise, and promises to reveal potential therapeutic options to improve pregnancy outcomes.