Maternal-Fetal Conflict During Infection: Lessons From a Mouse Model of Placental Malaria

Abstract

Infections that reach the placenta via maternal blood can target the fetal-placental barrier and are associated with reduced birth weight, increased stillbirth, miscarriage and perinatal mortality. Malaria during pregnancy can lead to infection of the placental tissue and to adverse effects on the unborn child even if the parasite is successfully cleared, indicating that placental sufficiency is significantly compromised. Human samples and animal models of placental malaria have been used to unravel mechanisms contributing to this insufficiency and have implicated molecular pathways related to inflammation, innate immunity and nutrient transport. Remarkably, fetal TLR4 was found to take part in placental responses that protect the fetus, in contrast to maternal TLR4 responses that presumably preserve the mother's health but result in reduced fetal viability. We propose that this conflict of fetal and maternal responses is a determinant of the clinical outcomes of placental malaria and that fetally derived trophoblasts are on the front lines of this conflict.

Keywords: malaria; maternal-fetal conflict; placenta; pregnancy; toll-like receptors.

Figure 1

(A) Cross section of a human placental terminal chorionic villus, which is part of highly branched tree of fetally derived tissue anchored in the chorionic plate and surrounded by maternal blood. At the terminal chorionic villi, the placental barrier is composed by the endothelial cells enclosed in mesenchyme followed by a layer of cytotrophoblasts and an outermost layer of syncytiotrophoblasts in contact with maternal blood. (B) Cross section of the analogous murine tissue, the placental labyrinth where the maternal fetal barrier is made up of a layer of fetal capillary endothelial cells, two layers of syncytiotrophoblasts and a discontinuous layer of mononuclear trophoblasts that is in direct contact with maternal blood. (C) In both the human and murine placentas, fetally derived syncytiotrophoblasts come into direct contact with maternal blood, an important similarity, as during a malaria infection, these are the fetal cells exposed to maternal inflammatory mediators and to components of parasite origin such as infected erythrocytes and microvesicles. (D) TLR4 detects and responds to several of these stimuli via either MyD88 or TRIF, activating several transcriptional factors including p38 and IRF3. (E) Transcriptional changes in the syncytiotrophoblast contribute to alterations in local production of vasoactivators such as nitric oxide, bradykinin and endothelin as well as altering nutrient transport pathways in a manner which result in fetal protection. In contrast, maternal responses impair these pathways and worsen the outcomes of pregnancy.