Abstract
BackgroundMalaria during pregnancy is characterized by the sequestration of malaria-infected red blood cells (iRBC) in the intervillous spaces of the placenta, often accompanied by the infiltration of maternal mononuclear cells, causing substantial maternal and foetal/infant morbidity. The iRBC bind to receptors expressed by the syncytiotrophoblast (ST). How ST responds to this interaction remains poorly understood. Because it is known that ST is immunoactive and can respond to infectious agents, the consequences of this ST-iRBC interaction should be investigated.MethodsAn in vitro system was used to assess the biochemical and immunological changes induced in ST by ST-adherent iRBCs. Changes in ST mitogen-activated protein kinase (MAPK) activation were assessed by immunoblotting and mRNA expression levels of selected cytokine and chemokines in primary ST bound by iRBC were determined using real-time, reverse transcription PCR. In addition, secreted cytokine and chemokine proteins were assayed by standard ELISA, and chemotaxis of PBMC was assessed using a two-chamber assay system.ResultsFollowing iRBC/ST interaction, ST C-Jun N-terminal kinase 1 (JNK1) was activated and modest increases in the mRNA expression of TGF-β and IL-8/CXCL8 were observed. In addition, this interaction increased secretion of MIF and MIP-1α/CCL3 by ST and induced migration of PBMC towards iRBC-stimulated ST.ConclusionResults from this study provide the first evidence that ST participates in shaping the local immunological milieu and in the recruitment of maternal immune cells to the maternal blood space during placental malaria infection.
Highlights
Malaria during pregnancy is characterized by the sequestration of malaria-infected red blood cells in the intervillous spaces of the placenta, often accompanied by the infiltration of maternal mononuclear cells, causing substantial maternal and foetal/infant morbidity
Stimulation of Jun N-terminal kinase 1 (JNK1) in ST cells by binding of iRBCST Increased phosphorylation of JNK1 (~2.5 fold increase) was evident after 30 minutes incubation of BeWoST with iRBCST (Figure 1). Incubation with both uRBC and iRBCST demonstrated slight increases in JNK1 activation (< 1.5 fold increases) within 5–15 minutes, but a greater than 2 fold increase was only observed in the presence of iRBCST 30 minutes post stimulation
Gene expression changes in ST stimulated with cytoadherence iRBCST To determine if the mitogen-activated protein kinase (MAPK) activation resulted in gene expression changes, several factors were selected for analysis by real-time PCR (Figure 2)
Summary
Malaria during pregnancy is characterized by the sequestration of malaria-infected red blood cells (iRBC) in the intervillous spaces of the placenta, often accompanied by the infiltration of maternal mononuclear cells, causing substantial maternal and foetal/infant morbidity. A hallmark of malaria during pregnancy is the sequestration of malaria-infected red blood cells (iRBCs) containing late developmental stages in the intervillous spaces (IVS) of the placenta [3,4,5]. This is usually accompanied by the infiltration of maternal leukocytes, especially monocytes,. PM poses substantial risk to the mother, the foetus, and the neonate in the form of maternal anaemia and poor foetal outcomes such as low birth weight (LBW) and prematurity ([9,10]; reviewed in [11,12])
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