Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the placenta can lead to fetal distress and demise, characterized by severe trophoblast necrosis, chronic histiocytic intervillositis (CHI), and massive perivillous fibrin deposition. We aimed to uncover spatial immune-related protein changes in SARS-CoV-2 placentitis compared with CHI placentas and uncomplicated pregnancies to gain insight into the underlying pathophysiological mechanisms. Placentas were retrospectively collected from cases with SARS-CoV-2 placentitis resulting in fetal distress/demise (n = 9), CHI (n = 9), and uncomplicated term controls (n = 9). The expression of 53 immune-related proteins was quantified using GeoMx Digital Spatial Profiler in three separate compartments: villi (fetal compartment), intervillous space, and decidua (both maternal compartments). Compared with controls, SARS-CoV-2 placentitis and CHI both displayed differentially expressed proteins in the intervillous space only, including upregulation of myeloid markers (e.g., CD40, CD11c, CD68, CD163). Specifically, SARS-CoV-2 placentitis was associated with reduced expression of multiple apoptotic proteins (e.g., BAD, BIM, BLXL, BCL6). In conclusion, SARS-CoV-2 placentitis and CHI are associated with enhanced myeloid cell infiltration into the intervillous space, but not in the decidua and villi. The more prominently reduced apoptosis-related protein expression in SARS-CoV-2 placentitis may lead to an exaggerated immune response, causing acute placental dysfunction and fetal demise.