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.
Age is among the strongest risk factors for severe outcomes from SARS-CoV-2 infection. We sought to evaluate associations between age and both mucosal and systemic host responses to SARS-CoV-2 infection. We profiled the upper respiratory tract (URT) and peripheral blood transcriptomes of 201 participants (age range of 1 week to 83 years), including 137 non-hospitalized individuals with mild SARS-CoV-2 infection and 64 uninfected individuals. Among uninfected children and adolescents, young age was associated with upregulation of innate and adaptive immune pathways within the URT, suggesting that young children are primed to mount robust mucosal immune responses to exogeneous respiratory pathogens. SARS-CoV-2 infection was associated with broad induction of innate and adaptive immune responses within the URT of children and adolescents. Peripheral blood responses among SARS-CoV-2-infected children and adolescents were dominated by interferon pathways, while upregulation of myeloid activation, inflammatory, and coagulation pathways was observed only in adults. Systemic symptoms among SARS-CoV-2-infected subjects were associated with blunted innate and adaptive immune responses in the URT and upregulation of many of these same pathways within peripheral blood. Finally, within individuals, robust URT immune responses were correlated with decreased peripheral immune activation, suggesting that effective immune responses in the URT may promote local viral control and limit systemic immune activation and symptoms. These findings demonstrate that there are differences in immune responses to SARS-CoV-2 across the lifespan, including between young children and adolescents, and suggest that these varied host responses contribute to observed differences in the clinical presentation of SARS-CoV-2 infection by age.
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