Potential pharmacologic interventions targeting TLR signaling in placental malaria

Abstract

Complications from placental malaria cause poor pregnancy outcomes, including low birthweight, preterm delivery, and stillbirths. Many of these complications are driven by maternal innate proinflammatory responses to the sequestration of Plasmodium falciparum in the placenta. However, recent studies show that, in reaction to maternal innate immune responses that are detrimental to the fetus, the fetus mounts innate immune counter-responses that ameliorate pregnancy outcomes. Such fetal-maternal conflict in placental malaria has potential for pharmacologic modulation for better pregnancy outcomes. Here, we discuss placental malaria pathogenesis, its complications, and the role of innate immunity and fetal-maternal innate immune conflict in placental malaria. Finally, we discuss pharmacologic immunomodulatory strategies and agents with the potential to improve placental malaria outcomes.

Keywords: fetal–maternal immune conflict; innate immune responses; placental malaria; pregnancy outcomes.

Figure 1. Schematic representation of events leading to human placental malaria and the hypothesized fetal-maternal innate immune conflict in response to placental malaria.

Infection with P. falciparum during pregnancy leads to malaria in pregnancy (A) and pregnant women are at higher risk of severe malaria, whose pathogenesis is driven by various factors including the rapture of infected P. falciparum-infected erythrocytes (IEs) and the release of P. falciparum (P.f.) DNA, hemozoin, and malaria endotoxin (a complex of hemozoin and parasite DNA) into maternal circulation. These factors activate proinflammatory factors like IL-6 and TNFα, which lead to systemic maternal inflammation and poor pregnancy outcomes (B), e.g., intrauterine growth restriction, low birthweight, preterm birth, and stillbirth. During malaria in pregnancy, IEs may sequester in the intervillous space, resulting in placental malaria. Placental malaria recruits macrophages and B-cells into the intervillous space, which, along with other factors like P.f. DNA and malaria endotoxin, activate maternal placenta TLR4 and cause strong placental inflammation that leads to poor pregnancy outcomes (C). These proinflammatory responses trigger a fetal counterresponse to placental malaria via the activation of fetal trophoblast TLR4 (D), which may improve pregnancy outcomes for the fetus (E)

Figure 2. Schematic representation of the impact of placental malaria on placenta function and potential interventions targeting mediators of impaired placental function during placental malaria.

Placental malaria causes poor pregnancy outcomes, including low birthweight, preterm birth, and stillbirth by triggering maternal placental inflammation through activation of maternal innate immunity mainly via TLR signaling and impairing placental perfusion by dysregulating vasoactive and angiogenic pathways in the placenta (A). Placental malaria outcomes can potentially be improved using immunomodulators of innate immune responses, such as TLR agonists and antagonists, and/or modulators or vasoactive/angiogenic processes, such as modulators of endothelin and/or bradykinin, VEGF inhibition, or supplementation of L-arginine, which may improve placental function (B).