title: Plasmodium falciparum malaria elicits inflammatory responses that dysregulate placental amino acid transport.
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.
authors: The University of Melbourne, Department of Medicine-RMH, Parkville, Victoria, Australia. pboeuf@unimelb.edu.au
authors: Philippe
authors: P
authors: Boeuf
authors: Elizabeth H
authors: EH
authors: Aitken
authors: Upeksha
authors: U
authors: Chandrasiri
authors: Caroline Lin Lin
authors: CL
authors: Chua
authors: Bernie
authors: B
authors: McInerney
authors: Leon
authors: L
authors: McQuade
authors: Michael
authors: M
authors: Duffy
authors: Malcolm
authors: M
authors: Molyneux
authors: Graham
authors: G
authors: Brown
authors: Jocelyn
authors: J
authors: Glazier
authors: Stephen J
authors: SJ
authors: Rogerson
mesh_terms: D000293:Adolescent; D000328:Adult; D026924:Amino Acid Transport System A / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000032:analysis / Q000378:metabolism*; D001692:Biological Transport; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007223:Infant; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism; D016778:Malaria, Falciparum / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D008295:Malawi; D008431:Maternal-Fetal Exchange / Q000276:immunology; D009000:Monocytes; D010920:Placenta / Q000276:immunology / Q000378:metabolism; D010922:Placenta Diseases / Q000276:immunology / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000276:immunology* / Q000502:physiology; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000276:immunology / Q000378:metabolism*; D055815:Young Adult
chemical_list: D026924:Amino Acid Transport System A; D000596:Amino Acids; D053583:Interleukin-1beta; C445761:SLC38A1 protein, human; C498797:SLC38A2 protein, human