Plasmodium falciparum malaria elicits inflammatory responses that dysregulate placental amino acid transport

PLoS Pathog. 2013 Feb;9(2):e1003153. doi: 10.1371/journal.ppat.1003153. Epub 2013 Feb 7.

Abstract

Placental malaria (PM) can lead to poor neonatal outcomes, including low birthweight due to fetal growth restriction (FGR), especially when associated with local inflammation (intervillositis or IV). The pathogenesis of PM-associated FGR is largely unknown, but in idiopathic FGR, impaired transplacental amino acid transport, especially through the system A group of amino acid transporters, has been implicated. We hypothesized that PM-associated FGR could result from impairment of transplacental amino acid transport triggered by IV. In a cohort of Malawian women and their infants, the expression and activity of system A (measured by Na⁺-dependent ¹⁴C-MeAIB uptake) were reduced in PM, especially when associated with IV, compared to uninfected placentas. In an in vitro model of PM with IV, placental cells exposed to monocyte/infected erythrocytes conditioned medium showed decreased system A activity. Amino acid concentrations analyzed by reversed phase ultra performance liquid chromatography in paired maternal and cord plasmas revealed specific alterations of amino acid transport by PM, especially with IV. Overall, our data suggest that the fetoplacental unit responds to PM by altering its placental amino acid transport to maintain adequate fetal growth. However, IV more profoundly compromises placental amino acid transport function, leading to FGR. Our study offers the first pathogenetic explanation for FGR in PM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Transport System A / genetics
  • Amino Acid Transport System A / metabolism
  • Amino Acids / analysis
  • Amino Acids / metabolism*
  • Biological Transport
  • Case-Control Studies
  • Cell Line, Tumor
  • Cohort Studies
  • Female
  • Fetal Growth Retardation / etiology
  • Fetal Growth Retardation / immunology
  • Fetal Growth Retardation / metabolism
  • Humans
  • Infant
  • Infant, Low Birth Weight
  • Infant, Newborn
  • Interleukin-1beta / blood
  • Interleukin-1beta / metabolism
  • Malaria, Falciparum / complications
  • Malaria, Falciparum / immunology
  • Malaria, Falciparum / metabolism*
  • Malawi
  • Maternal-Fetal Exchange / immunology
  • Monocytes
  • Placenta / immunology
  • Placenta / metabolism
  • Placenta Diseases / immunology
  • Placenta Diseases / metabolism*
  • Plasmodium falciparum / immunology*
  • Plasmodium falciparum / physiology
  • Pregnancy
  • Pregnancy Complications, Parasitic / immunology
  • Pregnancy Complications, Parasitic / metabolism*
  • Young Adult

Substances

  • Amino Acid Transport System A
  • Amino Acids
  • Interleukin-1beta
  • SLC38A1 protein, human
  • SLC38A2 protein, human

Grant support

These studies were funded by a project grant from the Australian National Health and Medical Research Council to SJR and JG (509185 www.nhmrc.gov.au), an Early Career Researcher Grant from the University of Melbourne to PB (600599 www.unimelb.edu.au) and a travel award from the Australian Society for Parasitology to PB (www.parasite.org.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.