Placental malaria is associated with a TLR–Endothelin-3–oxidative damage response in human placenta tissues

Placental malaria, which is mainly caused by the sequestration of Plasmodium falciparum -infected erythrocytes in the placenta, is an important driver of poor pregnancy outcomes, including fetal growth restriction, preterm birth, and stillbirth. However, the mechanisms underlying its adverse outcomes are unclear. Mouse models have previously shown that placental malaria (PM) triggers a proinflammatory response in the placenta, which is accompanied by a fetal Toll-like receptor (TLR)4-mediated innate immune response associated with improved fetal outcomes. Here, we used hematoxylin and eosin staining to identify PM-positive and negative samples in our biobank of placentas donated by women living in a malaria-endemic region of Kenya and assessed the impact of PM on the expression of TLRs, Endothelins, and oxidative damage. RT-qPCR analysis revealed that PM was associated with an upregulation of TLR4, TLR7, and Endothelin-3. Moreover, immunohistochemistry showed that PM was associated with elevated expression levels of the oxidative DNA damage marker, 8-hydroxy-2’-deoxyguanosine, while RT-qPCR revealed that this was accompanied by an upregulation of p21, an inhibitor of cell cycle progression and marker of cellular response to DNA damage. These findings allude to a novel mechanism of PM pathogenesis driven by a TLR–Endothelin-3–oxidative DNA damage signaling axis.