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

A high dimensional, multiomic analysis

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Dec 8 2021

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A small number of maternal SARS-CoV-2 infections are complicated by placentitis leading to obstetric complications, including fetal growth restriction and intra-uterine death. This study aims to understand the immunological processes that drive this potentially devastating condition.

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.

December 8, 2021


  • Approximately half of placentas from COVID-19 positive mothers with obstetric complications show direct infection of the trophoblast with SARS-CoV-2.
  • SARS-CoV-2+ COVID-19 placentitis shows a distinct immunopathological phenotype characterised by trophoblast necrosis, chronic histiocytic intervillousitis, T- & B-cell infiltrates & distinct cytikine profile.
  • Multiplex immunohistochemistry on the COMET™ platform combined with transcriptomic profiling can be used to validate novel markers and understand complex immunopathological phenomena.


Matthew Pugh, MD, PhD, FRCPath

Matthew Pugh, MD, PhD, FRCPath

Jean Shanks Pathsoc Intermediate Fellow and Associate Clinical Professor

University of Birmingham