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.

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

“…Mouse models of malaria indicate that TLR4, TLR7, and TLR9 are involved in detecting and responding to malaria infection [23,24]. Moreover, mouse models indicate that at the fetal-maternal interface, placental malaria activates TLR4-mediated immune responses that drive poor fetal outcomes, and that fetal TLR4-mediated counterresponses improve pregnancy outcomes [14,25,35]. However, this observation has not been previously made in human placental malaria.…”

Intravital imaging of host‐parasite interactions in organs of the thoracic and abdominopelvic cavities

“…These observations were confirmed by experiments showing that innate immune receptors expressed on trophoblasts (e.g.TLR4) contribute to in vitro engulfment of infected erythrocytes and to foetal protection during malaria infection (Rodrigues‐Duarte, Pandya, Neres, & Penha‐Gonçalves, ). These findings underpinned the hypothesis that innate immune recognition of Plasmodium infection by trophoblasts represents a foetus‐protective response that counteracts the pro‐inflammatory effects of the maternal immune system (Pandya & Penha‐Gonçalves, ). Nevertheless, the molecular wiring linking innate immune pathways and vasoregulation responses remains unexplored.…”

Self‐assembled human placental model from trophoblast stem cells in a dynamic organ‐on‐a‐chip system

“…Generally, animal models have great variations in the architecture of placenta from that in humans due to species differences. [5][6][7] The isolated explant cultures or primary placental cells could mimic the complex composition and structure of human placenta, [8][9][10] but the use of human tissue samples is limited due to ethical concerns of tissue availability, storage and manipulation. In vitro trophoblast cell culture models, such as BeWo 11,12 and Jeg-3 13,14 cell lines and human induced pluripotent stem cells (hiPSCs) 15 have been used to construct placental barrier, but they are often inadequate to recapitulate the complex placental architectures and functions due to abnormal cell phenotype or immature functions of trophoblasts.…”

“…Currently, various experimental models have been developed to study the response of human placenta to external stimulus. Generally, animal models have great variations in the architecture of placenta from that in humans due to species differences 5–7 . The isolated explant cultures or primary placental cells could mimic the complex composition and structure of human placenta, 8–10 but the use of human tissue samples is limited due to ethical concerns of tissue availability, storage and manipulation.…”