Investigations into malaria infection at the maternal-fetal interface and the characterization of placental polysialic acid

Author(s): Hromatka, Bethann S. | Advisor(s): Fisher, Susan J; Rosenthal, Philip J | Abstract: The human placenta is an organ that is derived from the fertilized embryo. It develops in advance of the embryo/fetus and through its specialized trophoblast populations, forms an "anchor" between mother and offspring. It carries out numerous important functions, including maintaining the pregnant state by secreting hormones and other molecules, and promoting tolerance of the genetically foreign (i.e., hemiallogeneic) embryo/fetus. The human placenta is bathed in maternal blood, which allows for nutrient uptake, waste elimination, and gas exchange. Finally, the placenta must defend the embryo/fetus from blood-borne pathogens. In this dissertation, I discuss placental malaria, which is characterized by the accumulation of parasitized erythrocytes at the maternal surface of the placenta. Although placental and congenital infection does not often occur (i.e., parasites are not usually found inside the placenta or embryo/fetus), infant low birth weight and pre-term labor are associated outcomes. Since examination of the placenta usually helps to explain an abnormal neonatal outcome, the characterization of Plasmodium falciparum-infected placental biopsies formed the basis of my studies. I carried out an in-depth histological analysis of samples obtained from pregnant women in Kinshasa, Democratic Republic of the Congo. These placentas, which were severely infected, displayed loss (necrosis) of syncytiotrophoblasts, the cells that cover the chorionic villi and form the primary barrier between maternal and fetal circulations. In parallel, I immunolocalized putative receptors for P. falciparum and my results suggested that histological changes (including syncytiotrophoblast loss) influenced their availability, such that many were only exposed in the infected state. Together, these results suggested that a reexamination of the mechanisms involved in initial adhesion was warranted and prompted me to carry out a binding screen to identify novel glycan receptors. P. falciparum-infected erythrocytes bound Lewis blood group antigens that were spatially and temporally positioned to initiate infection. Finally, I explored the possibility that parasitized erythrocytes might adhere to the uterine arterioles, which channel maternal blood to the intervillous space. Overall, my studies revealed that P. falciparum sequestration involves a complex series of interactions with both fetal and maternal cells, and is influenced by histological changes that expose receptors. As an offshoot, I also examined the role of Hofbauer cells, the fetal macrophage, in relationship to hemozoin, the byproduct of heme digestion by Plasmodium parasites. As my work on placental malaria familiarized me with glycobiology, I undertook a second project investigating the role of polysialic acid during placental development. Previous studies in the nervous and immune systems demonstrated that this cell-surface glycan has an enormous hydrated volume and globally modulates cell-cell interactions. In this dissertation, I showed that it is expressed by human placental trophoblasts and regulated as a function of gestational age--abundant early in pregnancy and barely detectable at term. It promoted cellular migration and invasion. Intriguingly, my results suggested that placental polysialic acid is associated with desmosomes, cell adhesion complexes. Together, these studies demonstrated that polysialic acid influences development of the human placenta.