862: Gene expression profiling of fetal Hofbauer cells and maternal intervillous macrophages in placental malaria.

Abstract

Placental malaria (PM) is a leading global cause of low birth weight infants from preterm delivery or fetal growth restriction. We previously showed that maternal and fetal macrophages in PM have distinct phenotypes. Here, we performed genome-wide transcriptional profiling of maternal intervillous macrophages (MIMs) and fetal Hofbauer cells (HBCs) in PM to characterize common and unique gene signatures. This is a nested prospective cohort study of women participating in a randomized controlled trial of antimalarial chemoprophylaxis in pregnancy in Tororo, Uganda, where 40% of women have PM at the time of delivery. HBCs and MIMs were purified from fresh placentas at the time of delivery, and total RNA was extracted from these paired samples. RNA sequencing was performed on 15 placentas (6 controls, 9 malaria cases). We determined differentially expressed (DE) genes due to PM in HBCs and MIMs using DESeq2 and Wald’s test (p≤0.05). Functional enrichment analysis was performed using DAVID to identify potential perturbed biological processes due to PM. We compared maternal and fetal macrophage responses to PM on the gene and pathway level. In comparing PM versus controls, we identified 1309 and 1535 DE genes in HBCs and MIMs, respectively. HBCs and MIMs had 166 DE genes in common. Significant enrichment of GO biological processes found in both fetal and maternal macrophages, included: female pregnancy, immune system development, cell-cell adhesion, and hemopoiesis. Further[Office1] analysis of DE genes within common enriched immune response pathways revealed malaria-specific responses at the gene level, e.g., CD83 expression decreased in maternal and fetal pairs. Our analyses also revealed unique responses to PM. For example, genes related to nucleic acid metabolic processes and cell cycle regulation were only observed to be perturbed in response to PM in MIMs, and not HBCs. Placental malaria is associated with differential gene expression signatures in MIMs and HBCs. Although many pathways were commonly regulated between these two cell types, we also identified differently regulated genes. These results suggested that maternal and fetal macrophages have distinct mechanisms of activation and transcriptional regulation in the setting of malaria infection.