The immune landscape of SARS-CoV-2-positive placentitis: a high dimensional, multiomic analysis.

Purpose of this study: A small number of maternal SARS-CoV-2 infections are complicated by placentitis leading to obstetric complications including foetal growth restriction and/or intra-uterine death. The aim of this study is to understand the immunological processes that drive this potentially devastating condition.

Methods: 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 hybridisation (ISH), bulk gene expression sequencing (GES) and GeoMX digital spatial profiling (DSP).

Results: 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. 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.

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