Spatial Analysis of Placentae During Congenital Cytomegalovirus Infection Reveals Distinct Cellular Profiles in Immune Cells and Trophoblasts

Cytomegalovirus (CMV) is the most common cause of birth defects by an infectious agent. Approximately 10% of infants with congenital CMV (cCMV) infection are symptomatic. Infected infants can exhibit long-term effects such as sensorineural hearing and vision loss and neurodevelopmental delay. To date, the mechanisms by which cCMV infection results in symptomatic disease are incompletely understood. The placenta has been implicated as a main thoroughfare for vertical transmission, as both placental immune cells and trophoblasts can be infected by CMV. The goal of this study was to spatially investigate changes in genes and proteins from immune cells and trophoblasts during cCMV infection. Utilizing the NanoString GeoMx Digital Spatial Profiler, we noted that both immune cells and trophoblasts in CMV ⁺ placentae exhibited increased expression and upregulation of immune activation receptors and pathways. Pro-apoptotic proteins were decreased in CMV ⁺ placentae, as were transcripts associated with cell death pathways. Spatially, immune cells infiltrating into CMV ⁺ placental villi had more CD4 ⁺ T cells expressing cell death markers than those T cells in the decidua (p = 0.002). In contrast, the decidua exhibited a CD8+ T cell abundance with far less upregulation of immune activation receptors than in the villi (p=0.03). These data can inform and direct future research into the immune mechanisms CMV uses to infect, evade, and vertically transmit the virus to the fetus.