Transcriptomic profiling of human placental explants exposed to Plasmodium falciparum reveals activation of tissue-remodeling pathways and signatures associated with the Placenta-Brain Axis.

BACKGROUND

Placental malaria contributes to adverse birth outcomes, preterm birth, intrauterine growth restriction, and low birth weight, yet the early molecular responses of the human placenta to Plasmodium falciparum remain poorly defined. The aim of this study was to explore the early transcriptional responses of human placental explants to P. falciparum infection using an in vitro co-culture model.

METHODS

Human placental explants were co-cultured with P. falciparum-infected erythrocytes. Tissue responses were evaluated through histopathology, LDH release assays, and transcriptomic profiling. RNA was extracted for downstream gene expression analysis, and differentially expressed genes were subjected to functional enrichment analysis.

RESULTS

Short-term exposure induced evident syncytiotrophoblast injury and increased LDH release. Transcriptomic profiling identified 197 differentially expressed genes, predominantly upregulated, involving pathways related to tissue remodeling, epithelial organization, angiogenesis, and metabolic regulation. Notably, several upregulated genes overlapped with transcriptional programs associated with the placenta-brain axis, including genes involved in neurotransmitter synthesis, calcium signaling, and synaptic organization. Downregulation of LPL suggested early disruption of placental lipid processing.

CONCLUSION

P. falciparum triggers structural and transcriptional remodeling in human placental tissue, affecting pathways essential for epithelial integrity, nutrient metabolism, and endocrine-neuroactive signaling. These molecular signatures provide a potential link between placental infection and long-term nutritional and neurodevelopmental outcomes observed in malaria-exposed children.