Intravital Placenta Imaging Reveals Microcirculatory Dynamics Impact on Sequestration and Phagocytosis of Plasmodium-Infected Erythrocytes

Luciana Vieira De Moraes,David N Olivieri,Iván Gómez-Conde,Carlos Eduardo Tadokoro,Carlos Penha-Gonçalves

doi:10.1371/journal.ppat.1003154

Luciana Vieira De Moraes, David N Olivieri + Show 3 more

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https://doi.org/10.1371/journal.ppat.1003154

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Abstract

Malaria in pregnancy is exquisitely aggressive, causing a range of adverse maternal and fetal outcomes prominently linked to Plasmodium-infected erythrocyte cytoadherence to fetal trophoblast. To elucidate the physiopathology of infected erythrocytes (IE) sequestration in the placenta we devised an experimental system for intravital placental examination of P. berghei-infected mice. BALB/c females were mated to C57Bl/6 CFP+ male mice and infected with GFP+ P. berghei IE, and at gestational day 18, placentas were exposed for time-lapse imaging acquisition under two-photon microscopy. Real-time images and quantitative measurements revealed that trophoblast conformational changes transiently restrain blood flow in the mouse placental labyrinth. The complex dynamics of placental microcirculation promotes IE accumulation in maternal blood spaces with low blood flow and allows the establishment of stable IE-trophoblast contacts. Further, we show that the fate of sequestered IE includes engulfment by both macrophagic and trophoblastic fetal-derived cells. These findings reinforce the current paradigm that IE interact with the trophoblast and provide definitive evidence on two novel pathogenesis mechanisms: (1) trophoblast layer controls placental microcirculation promoting IE sequestration; and (2) fetal-derived placental cells engulf sequestered IE.

Highlights

Infection with Plasmodium parasites during pregnancy is one of the leading causes of maternal and perinatal morbidity and mortality in malaria endemic areas and is severe in regions of unstable transmission [1]
The current placental malaria (PM) pathogenesis paradigm stipulates that accumulation of infected erythrocytes (IE) in human placenta elicits an inflammatory response [7,8,9] that is presumably responsible for pathological changes observed in the placental barrier, which has a negative impact on fetal growth and viability [10,11,12]
Malaria in pregnancy is exquisitely aggressive, causing a range of adverse effects impacting maternal and fetal health. Many of those effects are thought to derive from placental sequestration of red blood cells infected with the malaria parasite (Plasmodium falciparum) eliciting a placental inflammatory response that impairs maternal-fetal exchanges

Summary

Introduction

Infection with Plasmodium parasites during pregnancy is one of the leading causes of maternal and perinatal morbidity and mortality in malaria endemic areas and is severe in regions of unstable transmission [1]. The current placental malaria (PM) pathogenesis paradigm stipulates that accumulation of IE in human placenta elicits an inflammatory response [7,8,9] that is presumably responsible for pathological changes observed in the placental barrier (interhaemal membrane), which has a negative impact on fetal growth and viability [10,11,12]. This pathogenesis model is based on seminal findings that correlate human placental pathology with in vitro IE adhesion properties [13]. It is still unclear whether placental microcirculation contributes to establishment of in vivo IE-throphoblast interactions. Little is known of the fate of sequestered IE and the role of fetal components in the subsequent inflammatory response

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