title: Inhibition of placental mTOR signaling provides a link between placental malaria and reduced birthweight.
abstract: BACKGROUND
  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 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Medicine at Royal Melbourne Hospital, The University of Melbourne, Parkville, 3004, VIC, Australia. genelyn_dimasuay@yahoo.com.|Centre for Biomedical Research, Burnet Institute, 85 Commercial Road, Melbourne, 3004, VIC, Australia. genelyn_dimasuay@yahoo.com.
authors.forename: Kris Genelyn
authors.initials: KG
authors.lastname: Dimasuay
authors.affiliation: Department of Medicine at Royal Melbourne Hospital, The University of Melbourne, Parkville, 3004, VIC, Australia.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Aitken
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Fredrick
authors.initials: F
authors.lastname: Rosario
authors.affiliation: Department of Medicine at Royal Melbourne Hospital, The University of Melbourne, Parkville, 3004, VIC, Australia.
authors.forename: Madi
authors.initials: M
authors.lastname: Njie
authors.affiliation: Maternal and Fetal Health Research Centre, Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, St. Mary's Hospital, Manchester, UK.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Glazier
authors.affiliation: Department of Medicine at Royal Melbourne Hospital, The University of Melbourne, Parkville, 3004, VIC, Australia.|Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rogerson
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Road, Melbourne, 3004, VIC, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.|Department of Epidemiology and Preventive Medicine, Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Freya J I
authors.initials: FJ
authors.lastname: Fowkes
authors.affiliation: Department of Medicine at Royal Melbourne Hospital, The University of Melbourne, Parkville, 3004, VIC, Australia.|Centre for Biomedical Research, Burnet Institute, 85 Commercial Road, Melbourne, 3004, VIC, Australia.|Department of Microbiology and Central Clinical School, Monash University, Clayton, 3800, VIC, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.|Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Powell
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansson
authors.affiliation: Department of Medicine at Royal Melbourne Hospital, The University of Melbourne, Parkville, 3004, VIC, Australia. philippe.boeuf@burnet.edu.au.|Centre for Biomedical Research, Burnet Institute, 85 Commercial Road, Melbourne, 3004, VIC, Australia. philippe.boeuf@burnet.edu.au.|Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia. philippe.boeuf@burnet.edu.au.
authors.forename: Philippe
authors.identifier: http://orcid.org/0000-0002-5851-3373
authors.initials: P
authors.lastname: Boeuf
mesh_terms: D001724:Birth Weight / Q000502:physiology; D005260:Female; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D010920:Placenta / Q000378:metabolism* / Q000469:parasitology; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Deptor; Fetal growth restriction; Intervillositis; System A transporter