Abstract / Summary
Maternal systemic infection during pregnancy is associated with placental dysfunction even when pathogens do not directly invade the placenta, but the cellular pathways linking antecedent infection to persistent placental alterations remain poorly defined. Here we used spatial transcriptomics to resolve trophoblast-, fetal endothelial, and Hofbauer cell-enriched niches in placentas collected at term after clinical recovery from antepartum pyelonephritis. We profiled 168 spatially defined areas from 14 placentas and integrated transcriptional findings with blinded histopathology and quantitative extracellular matrix analysis. Pyelonephritis was associated with strikingly compartment-specific transcriptional responses. Hofbauer cell-enriched niches showed the most extensive alterations, with coordinated enrichment of extracellular matrix remodeling and vascular developmental programs, including increased ELN expression (log2FC = 0.84, FDR = 0.033) and increased expression of genes governing collagen deposition, elastic-fiber assembly, matrix maturation and turnover. Quantitative analysis of 1,790 fetal vessels independently identified altered perivascular matrix composition, with Hofbauer cell-enriched ELN expression correlating with greater perivascular elastin content ({rho} = 0.67, P = 0.008). Fetal endothelial-enriched regions exhibited complementary alterations in vascular remodeling and endothelial identity, including increased PLAC8 (log2FC = 1.36, FDR = 0.047), whereas trophoblast-enriched regions showed little detectable transcriptional response. Histopathology further demonstrated increased lesions associated with maternal vascular malperfusion and perivillous fibrin deposition. Together, these findings identify the villous immune-stromal-vascular microenvironment as a persistent site of placental remodeling following maternal infection and suggest that clinical recovery from maternal illness may not coincide with normalization of placental biology.