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Malaria-associated changes in fetal syncytiotrophoblast function

By Winifrida Benedict Kidima

Abstract

Ph.D. University of Hawaii at Manoa 2013.Includes bibliographical references.The fetus is entirely dependent on syncytiotrophoblasts (ST) that line the intervillous space (IVS) of the placenta as ST play a critical role in fetal development. During placental malaria (PM), Plasmodium falciparum infected erythrocytes (IE) bind to ST causing inflammation; leading to low birth weight babies due to fetal growth restriction (FGR) and preterm delivery (PTD). We hypothesize that the microenvironment that prevails during PM alters ST functions that are important for fetus growth. We conducted genome-wide expression studies of fetal cells from PM-infected placentas to investigate whether changes occur in fetal cells during to PM. We then developed a protocol and established an in vitro system to investigate if the changes identified in vivo were occurring in ST. The BeWo cell line with characteristics of ST was co-cultured with CS2 IE, schizogonic products, cytokines and chemokines prepared in vitro by co-culturing THP-1IE. Our microarray data showed that insulin like growth factor 1(IGF-1), insulin, mammalian target of ramphamycin (mTOR), vascular endothelia growth factor (VEGF), transforming growth factor 1 (TGFβ1), epidermal growth factor (EGF) and prostaglandin synthesis and regulation signaling pathways were significantly (p≤ 0.05) dysregulated in fetal cells from chronically PM-infected placentas. Several genes (leptin, system A amino acid transporters and placental 11beta-hydroxysteroud dehydorogenase-2-gene) known to be important in fetal growth) were also downregulated. In vitro results demonstrated that optimal response of BeWo cell line to CS2 IE occurred when BeWo were treated with 10μM forskolin for 72 hrs and cultured with 10 IE: 1 BeWo for 48 hrs. Using the same protocol, we showed inflammatory cytokines and chemokines, but not IE or IE with schizogonic products, significantly altered genes linked with vasculogenesis, blood vessel formation and negative regulation of vasoconstriction. Interestingly, cytokines and chemokines significantly dysregulated growth pathways similar to those that were altered in chronically infected placentas, including IGF1, insulin, mTOR. TGFβ1, EGF, platelet derived growth factor and prostaglandin synthesis. We concluded that perturbation of ST functions by the cytokines and chemokines secreted by maternal cells upon exposure to IE explains the biological mechanisms that lead to increased risk of FGR during chronic PM

Topics: placental malaria, fetal growth restriction, preterm delivery, microenvironment
Publisher: [Honolulu] : [University of Hawaii at Manoa], [December 2013]
Year: 2013
OAI identifier: oai:scholarspace.manoa.hawaii.edu:10125/100714
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