Spatial Transcriptomic Profiling of the Human Placenta in Congenital Cytomegalovirus Infection: A Broad Antiviral Response with Concurrent Suppression of Trophoblast and Vascular Programs

Abstract

Congenital cytomegalovirus (CMV) is the most common congenital infection and a leading infectious cause of childhood hearing loss and neurodevelopmental disability. The cellular organization of the placental response to infection is incompletely defined. We applied Visium CytAssist spatial transcriptomics to formalin-fixed tissue from two CMV-infected and two uninfected late-gestation placentas and annotated the major maternal and fetal cell populations by reference-based label transfer. Across 16,074 spatial spots, the only significant compositional changes were increased T cell spots and decreased syncytiotrophoblast-enriched spots in CMV-infected placentas; the remaining populations showed similar changes but did not reach significance. Differential expression comparing CMV-infected to uninfected samples within each cell type identified two opposing programs. Infected placentas displayed a broad interferon-stimulated gene signature accompanied by induction of CXCR3-ligand chemokines, antigen-processing machinery, and the major histocompatibility complex class I transactivator NLRC5, classical-pathway complement components, and lymphocyte and plasma-cell markers, most pronounced in endothelial, stromal, and syncytiotrophoblast clusters and minimal in extravillous trophoblasts. Concurrently, infected placentas showed downregulation of trophoblast differentiation and syncytialization genes, including PAPPA2, pregnancy-specific glycoproteins, CGA, and GCM1, as well as vascular and hemostatic genes, including FLT1, VEGFA, PECAM1, and TFPI2. These data provide a cell-type-resolved molecular correlation of immune activation and placental dysfunction associated with congenital CMV. Together, the data indicate that congenital CMV infection is associated with a coordinated shift at the maternal–fetal interface, in which a broad interferon-driven immune response accompanies suppression of trophoblast-developmental and vascular programs, providing a cell-type-resolved reference for larger studies of placental CMV transmission. Future studies in larger cohorts will be needed to confirm these findings.