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.
Highlights
Pregnant women are at a higher risk of malaria infection (Espinosa et al, 2000; Lindsay et al, 2000)
Experimental demonstration of the pathogenic mechanisms operating in the placenta relies on available mouse models of disease. In this perspective article we explore evidence generated from a mouse model of acute placental malaria that highlights the role of toll-like receptor 4 (TLR4) in controlling the outcomes of pregnancy ergo providing an interesting example of infection provoking conflict between the mother and the unborn child
It is expected that a variety of pathways are impacted upon during placental infection, affecting inflammatory responses, nutrient transport and vasoregulatory responses, and contributing to placental insufficiency that leads to poor pregnancy outcomes
Summary
Pregnant women are at a higher risk of malaria infection (Espinosa et al, 2000; Lindsay et al, 2000). Earlier studies have highlighted a potential role for vascular endothelial growth factor (VEGF) and its receptors in the response to placental malaria in primigravid mothers, with soluble receptors for VEGF being more abundantly expressed in the placenta This further implicates circulatory impairments in the disease pathology and provides the first evidence that placental responses to infection may not be in harmony with maternal responses, as maternal cells in the placenta showed elevated VEGF levels whereas fetal syncytiotrophoblasts produced more sVEGFR1, reducing VEGF bioavailability (Muehlenbachs et al, 2006). These findings suggest that the intertwining of inflammatory signals, vasoregulatory systems, and nutrient transport pathways in the placenta are critical components of human placental malaria pathophysiology. In this perspective article we explore evidence generated from a mouse model of acute placental malaria that highlights the role of toll-like receptor 4 (TLR4) in controlling the outcomes of pregnancy ergo providing an interesting example of infection provoking conflict between the mother and the unborn child
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