Poster Presentation Lorne Infection and Immunity 2014

Placental mTOR signalling and foetal growth restriction in placental malaria (#132)

Genelyn Dimasuay 1 , Thomas Jansson 2 , Jocelyn Glazier 3 , Stephen Rogerson 1 4 , Philippe Boeuf 1 4
  1. Department of Medicine (RMH), The University of Melbourne, Parkville, VIC, Australia
  2. Department of Obstetrics and Gynecology, University of Texas Health Science Centre, San Antonio, Texas, United States of America
  3. Maternal and Foetal Health Research Centre, University of Manchester, St. Mary's Hospital, Manchester, United Kingdom
  4. Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia

Placental malaria, especially when associated with a local inflammatory response termed intervillositis, can cause foetal growth restriction leading to low birth weight. We have identified decreased transplacental amino acid transport capacity as a mechanism leading to foetal growth restriction in placental malaria. The mechanistic target of rapamycin (mTOR) pathway regulates placental amino acid uptake in response to various environmental cues.

We hypothesize that the impaired amino acid transport capacity observed in placental malaria infection with intervillositis is mediated by a down-regulation of placental mTOR signalling activity, contributing to poor foetal growth.

Term villous tissue biopsies from uninfected placentas and from infected placentas with and without intervillositis (n=4/group) from Malawian women were used. We assessed mTOR signalling activity by quantifying the expression and phosphorylation levels of downstream effectors of the mTOR pathway namely ribosomal protein S6 (rpS6) and eukaryotic initiation factor 4E binding protein 1 (4EBP-1) using western blot.

The mTOR activity appears to be down-regulated in placental malaria especially with intervillositis. Relative phosphorylation levels of 4EBP-1 are significantly lower in infected placentas compared to uninfected tissues (p = 0.04) while the lowest relative phosphorylation levels of rpS6 are specifically found in inflamed placentas (p = 0.04) compared to placentas without inflammation. Relative phosphorylation levels of rpS6 negatively correlate with the severity of the inflammation measured as the percentage of monocytes in placental blood
(R = -0.85; p = 0.007) and positively with birth weight (R = 0.75; p = 0.03).

These results suggest that placental malaria, especially with intervillositis, is associated with a down-regulation of placental mTOR signalling activity, supporting foetal growth restriction.

Identifying mTOR as a central regulator of foetal growth in placental malaria would pave the way for innovative intervention strategies, including supplementation with nutrients that specifically activate placental mTOR signalling, to improve foetal growth and pregnancy outcomes in women with malaria.