Inhibition of placental mTOR signaling provides a link between placental malaria and reduced birthweight

Abstract

BackgroundPlacental Plasmodium falciparum malaria can trigger intervillositis, a local inflammatory response more strongly associated with low birthweight than placental malaria infection alone. Fetal growth (and therefore birthweight) is dependent on placental amino acid transport, which is impaired in placental malaria-associated intervillositis. Here, we tested the hypothesis that mechanistic target of rapamycin (mTOR) signaling, a pathway known to regulate amino acid transport, is inhibited in placental malaria-associated intervillositis, contributing to lower birthweight.MethodsWe determined the link between intervillositis, mTOR signaling activity, and amino acid uptake in tissue biopsies from both uninfected placentas and malaria-infected placentas with and without intervillositis, and in an in vitro model using primary human trophoblast (PHT) cells.ResultsWe demonstrated that (1) placental mTOR activity is lower in cases of placental malaria with intervillositis, (2) placental mTOR activity is negatively correlated with the degree of inflammation, and (3) inhibition of placental mTOR activity is associated with reduced placental amino acid uptake and lower birthweight. In PHT cells, we showed that (1) inhibition of mTOR signaling is a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake and (2) constitutive mTOR activation partially restores amino acid uptake.ConclusionsOur data support the concept that inhibition of placental mTOR signaling constitutes a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake, which may contribute to lower birthweight. Restoring placental mTOR signaling in placental malaria may increase birthweight and improve neonatal survival, representing a new potential therapeutic approach.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0759-3) contains supplementary material, which is available to authorized users.

Oxidative Stress: A Potential Therapeutic Target in Placental Malaria

“…At moderate levels, HNE promotes organelle and protein damage leading to induction of autophagy (45). Inhibition of mTOR signaling has recently been shown to provide a link between human PM and low birth weight (46), but has not been explored in the context of malaria-induced oxidative stress.…”

Uptake of intermittent preventive treatment for malaria during pregnancy with Sulphadoxine-Pyrimethamine in Malawi after adoption of updated World Health Organization policy: an analysis of demographic and health survey 2015–2016

“…Pregnant women are susceptible to severe Plasmodium falciparum infection because of alteration of acquired antimalarial immunity due to parasites (VAR2CSA) that sequester in the placenta [7,8]. The Plasmodium falciparum impairs the capacity of the placenta to transport amino acids from maternal blood to the foetus, and therefore contributing to low birth weights (LBW) [9]. Other consequences of malaria infection in pregnancy are increased risk of severe anaemia, cerebral malaria, pre-term delivery, intrauterine growth retardation, maternal death and increased risk to unborn baby from miscarriage [10][11][12][13].…”

Integrated Proteomics Reveals Apoptosis-related Mechanisms Associated with Placental Malaria*

“…In contrast to our findings, a previous study by Dimasuay et al had demonstrated that the activity of both mTOR complexes is decreased in placental malaria with intervillositis, as evidenced by the reduced content of mTORC1 downstream products phosphoS6 and phospho4EBP1 and mTORC2 downstream product phosphoAKT S473. In addition, they also showed that mTOR inhibition was associated to high levels of the cytokines IL-1␤, IL-6, IL-8, TNF and IL-10 which are secreted by monocytes exposed to infected erythrocytes (40). A possible reason to explain the discrepancy in mTORC1 and 2 activities between both studies relies in the fact that, in contrast to Dimasuay et al (40), our experiments were performed in past-infected placentas where no parasites or intervillositis were found (supplemental Table S2).…”

“…It is well known that fetal growth is directly related to maternal nutrient availability and ability to transport these nutrients from maternal circulation to the fetus (35,36). The rupture of amino acid transport in malaria-infected placentas with intervillositis was recently correlated with reduced birth weight (40). Moreover, protein folding and protein catabolic process (ubiquitin-dependent protein catabolism, proteasomal protein catabolism) are also important biological processes related to cell metabolism, survival, and adaptation to cell stress (41,42).…”