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

Kris Genelyn Dimasuay,Jocelyn Glazier,Philippe Boeuf,James G Beeson,Fredrick Rosario,Madi Njie,Thomas Jansson,Stephen J Rogerson,Theresa Powell,Elizabeth H Aitken,Freya J I Fowkes

doi:10.1186/s12916-016-0759-3

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.

Highlights

Placental Plasmodium falciparum malaria can trigger intervillositis, a local inflammatory response more strongly associated with low birthweight than placental malaria infection alone
We previously demonstrated that placental malaria-associated intervillositis reduced both the expression and activity of System A transporters, and that System A activity and birthweight are positively correlated in placental malaria [12]
We provide for the first time evidence that inhibition of mechanistic target of rapamycin (mTOR) signaling is a mechanistic link between placental malaria-associated intervillositis and decreased amino acid transport, contributing to lower birthweight

Summary

Introduction

Placental Plasmodium falciparum malaria can trigger intervillositis, a local inflammatory response more strongly associated with low birthweight than placental malaria infection alone. Fetal growth (and birthweight) is dependent on placental amino acid transport, which is impaired in placental malaria-associated intervillositis. Malaria in pregnancy can lead to placental malaria characterized by the sequestration of P. falciparum-infected erythrocytes in the maternal intervillous blood space of the placenta. This can trigger the recruitment and activation of maternal immune cells, resulting in a local inflammatory response termed intervillositis. The underlying mechanisms linking placental malaria-associated intervillositis and decreased birthweight are unknown, which hinders the development of intervention strategies aimed at improving the birthweight of infants born to malaria-infected women. There is a significant and urgent need for additional interventions aimed directly at improving birthweight that can complement existing malaria control strategies

Objectives

Methods

Results

Discussion

Conclusion