Low birthweight is the main risk factor in 80% of neonatal deaths. Despite current interventions, malaria in pregnancy is still a major contributor, causing approximately 900,000 low birthweight deliveries yearly, mainly by restricting fetal growth. Current antimalarial strategies are largely inefficient at improving the growth and birthweight of fetuses born to malaria-infected mothers. Interventions targetting the pathological mechanisms of fetal growth restriction in placental malaria are urgently needed.
The strongest determinant of fetal growth is amino acid supply, which depends on the capacity of the placenta to transport amino acids to the fetus. Placental amino acid transport is positively regulated by the mechanistic Target of Rapamycin (mTOR) pathway, itself inhibited by inflammation.
We hypothesized that inflammatory response to placental malaria inhibits placental mTOR signalling, decreasing placental amino acid transport, contributing to poor fetal growth.
Delivery placental tissue biopsies sampled from Malawian women were grouped into uninfected control placentas and cases of placental malaria without and with inflammatory response.
Compared to the other two histological groups, placental malaria-associated inflammation was specifically associated with decreased placental mTOR activity, which positively correlated with the density of the inflammation and negatively correlated with placental amino acid transport. This demonstrated a strong association between the inflammatory responses to placental malaria, placental mTOR signalling inhibition and decreased amino acid transport.
In an in vitro model of placental malaria-associated inflammation using primary human trophoblast cells, we showed that mTOR signalling is inhibited in response to placental malaria-associated inflammation, causing decreased amino acid uptake.
Our data strongly support mTOR as a mechanistic link between placental malaria-associated inflammation and fetal growth restriction. This opens the way to interventions aimed at improving fetal growth by restoring mTOR activity through nutritional mTOR activators.