Dysregulation of placental ABC transporters in a murine model of malaria-induced preterm labor

Abstract

Malaria in Pregnancy (MiP) is characterized by placental accumulation of Plasmodium -infected erythrocytes, intrauterine growth restriction (IUGR) and preterm delivery (PTD). Placental ATP-binding cassette (ABC) transporters mediate the efflux of nutrients, cytokines and xenobiotics. The expression and activity of these transporters are highly responsive to infection. We hypothesized that MiP would perturb the expression of placental ABC transporters, promoting PTD. Peripheral blood, spleens, livers and placentas of pregnant mice, infected with Plasmodium berghei ANKA on gestational day (GD) 13.5, were collected and analyzed on GD18.5. The primary consequences of human MiP, including IUGR, PTD (20%) and placental inflammation, were recapitulated in our mouse model. Electron microscopy revealed attenuated presence of labyrinthine microvilli and dilated spongiotrophoblasts -granular endoplasmic reticulum cisternae. Additionally, a decrease in placental Abca1 ( ABCA1), Abcb1b ( P-glycoprotein), Abcb9 and Abcg2 ( BCRP) expression was observed in MiP mice. In conclusion, MiP associated with PTD impairs placental ABC transporters’ expression, potentially modulating placental nutrient, environmental toxin and xenobiotic biodistribution within the fetal compartment, and may, at some degree, be involved with pregnancy outcome in MiP.

Malaria in pregnancy regulates P‐glycoprotein (P‐gp/Abcb1a) and ABCA1 efflux transporters in the Mouse Visceral Yolk Sac

“…9 In the previous study, we provided evidence that MiP has the potential to increase foetal exposure to drugs and environmental toxins, via down-regulation of major placental drug and nutrient ABC efflux transporters. 9 Moreover, other studies have demonstrated the sensitivity of placental P-gp and BCRP to infection. C57BL/6 mice exposed to sublethal (foetal) LPS in mid-pregnancy, exhibited impaired placental P-gp activity, 18 while polyinosinic:polycytidylic acid (PolyI:C, a viral mimic) had no effect on placental P-gp activity.…”

“…In this context, the MIF chemokine is present at high levels in the amniotic fluid of women in PTL with infection and its expression is increased in chorioamniotic membranes during infection. 39The pattern of the pro-inflammatory response observed in the yolk sac is in contrast with our previous report showing placental up-regulation of Cxcl1 and Ccl2, induced by MiP 9. Together, these results suggest that the yolk sac mounts a blunted pro-inflammatory response to systemic malarial infection when compared to the placenta.…”

Malaria in pregnancy regulates P-glycoprotein (P-gp/Abcb1a) and ABCA1 efflux transporters in the mouse visceral yolk sac

“…An animal model of severe experimental malaria, which recapitulates many of the features of the human malarial disease in pregnancy, including placental malarial, IUGR, low birth weight and PTL was used as previously described [9]. This model resulted in a 20% rate of PTL in infected dams, however, all analyses were undertaken in the yolk sac of fetuses born at GD18.5 (i.e.…”

“…MiP is characterized by adherence of Plasmodium falciparum-infected erythrocytes to specific syncytiotrophoblast glycosaminoglycans; a condition referred to as "placental malaria" [3,4]. In response, the placental barrier may undergo various adaptive changes that comprise activation and migration of immune cells, alteration of cytokine and chemokine output [2,5], intervillositis, decreased enrichment of syncytiotrophoblast-microvilli and lower expression of placental glucose (GLUT1), amino acid (SNAT1, SNAT2, Cat1, Lat1 and 4F2hc), solute carrier (SLC) drug uptake (Oatp2b1, Oct3, Ent1 and Ent2) and nutrient/drug efflux ABC transport systems (ABCA1, BCRP and P-gp) [6][7][8][9][10][11].…”

“…Its disruption has been associated with IUGR, PTL, pre-eclampsia and chorioamnionitis [13,[15][16][17]. In this context, reports from different groups have demonstrated that it participates in the adaptive trophoblastic responses to maternal infection [9,12,14,[16][17][18]. Comprised of 50 transporters divided into seven sub-classes ranging from ABCA through ABCG [19], these transmembrane transporters are expressed in different cell types, including those from biological barriers [12].…”