Effects of Plasmodium falciparum on Placental Expression of Inflammatory and Coagulation Factors

Abstract

Plasmodium falciparum infection during pregnancy, which can develop into placental malaria (PM), is estimated to cause over 200,000 infant deaths annually. PM is characterized by sequestration of parasite infected red blood cells (iRBCs) and deposition of hemozoin (HZ) in the maternal blood (intervillous) space of the placenta. HZ is an insoluble, iron‐containing by‐product of the parasite's digestion of hemoglobin. Additionally, accumulation of maternal immune cells and excessive deposition of fibrin are seen in the intervillous space. The role of the syncytiotrophoblast (ST), the outermost cell layer of the placenta, during PM pathogenesis remains unclear. It is hypothesized that the ST responds to iRBCs, HZ, and inflammatory cytokines like tumor necrosis factor (TNF) produced by maternal immune cells to attenuate infection. However, it is ultimately harmed by its own response. Mechanistically, it is predicted that TNF leads to activation of tissue factor (TF), the initiator of the extrinsic coagulation pathway, which ultimately results in fibrin deposition. In addition to TNF, HZ released from iRBCs may also upregulate TF. Downstream coagulation factors activate protease activated receptors (PARs), which are G‐protein coupled receptors highly expressed on the ST. Activated PARs increase expression of TNF, propagating what is known as “the inflammation‐coagulation cycle”. The cycle's propagation adversely affects nutrient and gas exchange between the maternal blood and the ST, resulting in growth restriction, low birth weight, and occasionally death of the fetus. Using a human choriocarcinoma cell line, BeWo, and isolated human trophoblast cells, in vivo host (ST)‐parasite interactions are simulated. BeWos and human trophoblasts are left unstimulated or stimulated over a physiologically relevant time‐course with (1) lipopolysaccharide (LPS; positive control), (2) natural HZ, (3) TNF, or (4) natural HZ/TNF. RNA isolation is followed by cDNA generation and qPCR for TF, PAR‐1, and PAR‐2. Results indicate that BeWos respond to LPS and HZ with a modest upregulation of TF and PAR‐1 between 2 to 4 hours. Response to TNF occurs at 2 hours with a modest upregulation of TF. Gene expression of PAR‐2 was not found to be significant over the time‐course. qPCR results with cDNA generated from time‐course experiments using human trophoblast cells are forthcoming. Identifying the extent to which the ST is involved in PM pathogenesis will advanced the understanding of how this syndrome impacts fetal development and outcome.Support or Funding InformationThis work is supported by National Institutes of Health grant 1R21AI111242 to Dr. Julie M. Moore.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.