The immune landscape of SARS-CoV-2-positive placentitis

FFPE tissue from 13 cases of placentitis from mothers with COVID-19, 6 diseased controls (chronic histiocytic villousitis (CHI) and villousitis of unknown origin (VUE), and 5 normal placentas were examined by high-plex 32 marker immunohistochemistry (mIHC) on the Lunaphore COMET™ platform. Transcriptomic profiling was performed by RNAscope in-situ hybridization (ISH), bulk gene expression sequencing (GES), and GeoMX digital spatial profiling (DSP).

Direct SARS-CoV-2 infection of the trophoblast was demonstrated in 6/13 cases from SARS-CoV-2 positive mothers by mIHC (dual positivity for viral spike and nucleocapsid proteins) and confirmed by ISH and bulk GES. The virus was also detected within histiocytes consistent with virus phagocytosis. SARS-CoV-2+ cases of placentitis showed a predominantly histiocytic (CD68+) intervillous infiltrate with an associated smaller population of T-cells (CD3+) and B-cells (CD20+), distinguishing COVID-19 placentitis from diseased controls. GES showed upregulation of the CXCL10 and type I interferon pathways. CXCL10 expression within histiocytes was confirmed by mIHC and RNAscope.

SARS-CoV-2 can directly infect the placental villous trophoblast. SARS-CoV-2 placentitis is characterized by chronic histiocytic intervillousitis and high CXCL10 production and activation of type I interferon signaling pathways. Overall, SARS-CoV-2 positive placentas showed a distinct immunopathological phenotype compared to SARS-CoV-2 negative placentas from COVID-19 positive mothers and disease controls.