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SARS-CoV2 vertical transmission with adverse effects on the newborn revealed through integrated immunohistochemical, electron microscopy and molecular analyses of Placenta.
EBioMedicine. 2020 Sep; 59:102951.E

Abstract

BACKGROUND

. The occurrence of trans-placental transmission of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection remains highly debated. Placental positivity for SARS-CoV-2 has been reported in selected cases, but infection or virus-associated disease of fetal tissues or newborns remains to be demonstrated.

METHODS

We screened for SARS-CoV-2 spike (S) protein expression placentas from 101 women who delivered between February 7 and May 15, 2020, including 15 tested positive for SARS-CoV-2 RNA, 34 tested negative, and 52 not evaluated as they did not meet testing criteria (32), or delivered before COVID-19 pandemic declaration (20). Immunostain for SARS-CoV-2 nucleocapsid (N) was performed in the placentas of all COVID-19 positive women. One placenta resulted positive for the SARS-CoV-2 S and N proteins, which was further studied by RNA-in situ hybridization and RT-PCR for S transcripts, and by electron microscopy. A comprehensive immunohistochemical and immunofluorescence analysis of the placental inflammatory infiltrate completed the investigations.

FINDINGS

SARS-CoV-2 S and N proteins were strongly expressed in the placenta of a COVID-19 pregnant woman whose newborn tested positive for viral RNA and developed COVID-19 pneumonia soon after birth. SARS-CoV-2 antigens, RNA and/or particles morphologically consistent with coronavirus were identified in villous syncytiotrophoblast, endothelial cells, fibroblasts, in maternal macrophages, and in Hofbauer cells and fetal intravascular mononuclear cells. The placenta intervillous inflammatory infiltrate consisted of neutrophils and monocyte-macrophages expressing activation markers. Absence of villitis was associated with an increase in the number of Hofbauer cells, which expressed PD-L1. Scattered neutrophil extracellular traps (NETs) were identified by immunofluorescence.

INTERPRETATION

We provide first-time evidence for maternal-fetal transmission of SARS-CoV-2, likely propagated by circulating virus-infected fetal mononuclear cells. Placenta infection was associated with recruitment of maternal inflammatory cells in the intervillous space, without villitis. PD-L1 expression in syncytiotrophoblast and Hofbaeur cells, together with limited production of NETs, may have prevented immune cell-driven placental damage, ensuring sufficient maternal-fetus nutrient exchanges.

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Authors+Show Affiliations

Facchetti F
Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy. Electronic address: fabio.facchetti@unibs.it.
Bugatti M
Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
Drera E
Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
Tripodo C
Tumor Immunology Unit, Department of Health Sciences, University of Palermo School of Medicine, 90134, Palermo, Italy.
Sartori E
Department of Obstetrics and Gynaecology, University of Brescia, 25123, Brescia, Italy.
Cancila V
Tumor Immunology Unit, Department of Health Sciences, University of Palermo School of Medicine, 90134, Palermo, Italy.
Papaccio M
Department of Obstetrics and Gynaecology, University of Brescia, 25123, Brescia, Italy.
Castellani R
Department of Obstetrics and Gynaecology, University of Brescia, 25123, Brescia, Italy.
Casola S
The FIRC Institute of Molecular Oncology (IFOM), 20139, Milan, Italy.
Boniotti MB
Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna (I.Z.S.L.E.R.), 25124 Brescia, Italy.
Cavadini P
Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna (I.Z.S.L.E.R.), 25124 Brescia, Italy.
Lavazza A
Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna (I.Z.S.L.E.R.), 25124 Brescia, Italy.

MeSH

AdultBetacoronavirusCOVID-19Coronavirus InfectionsCoronavirus Nucleocapsid ProteinsExtracellular TrapsFemaleHumansImmunohistochemistryInfant, NewbornMacrophagesMicroscopy, ElectronNasopharynxNucleocapsid ProteinsPandemicsPhosphoproteinsPlacentaPneumonia, ViralPregnancyRNA, ViralSARS-CoV-2Spike Glycoprotein, Coronavirus

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32818801

Citation

Facchetti, Fabio, et al. "SARS-CoV2 Vertical Transmission With Adverse Effects On the Newborn Revealed Through Integrated Immunohistochemical, Electron Microscopy and Molecular Analyses of Placenta." EBioMedicine, vol. 59, 2020, p. 102951.
Facchetti F, Bugatti M, Drera E, et al. SARS-CoV2 vertical transmission with adverse effects on the newborn revealed through integrated immunohistochemical, electron microscopy and molecular analyses of Placenta. EBioMedicine. 2020;59:102951.
Facchetti, F., Bugatti, M., Drera, E., Tripodo, C., Sartori, E., Cancila, V., Papaccio, M., Castellani, R., Casola, S., Boniotti, M. B., Cavadini, P., & Lavazza, A. (2020). SARS-CoV2 vertical transmission with adverse effects on the newborn revealed through integrated immunohistochemical, electron microscopy and molecular analyses of Placenta. EBioMedicine, 59, 102951. https://doi.org/10.1016/j.ebiom.2020.102951
Facchetti F, et al. SARS-CoV2 Vertical Transmission With Adverse Effects On the Newborn Revealed Through Integrated Immunohistochemical, Electron Microscopy and Molecular Analyses of Placenta. EBioMedicine. 2020;59:102951. PubMed PMID: 32818801.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV2 vertical transmission with adverse effects on the newborn revealed through integrated immunohistochemical, electron microscopy and molecular analyses of Placenta. AU - Facchetti,Fabio, AU - Bugatti,Mattia, AU - Drera,Emma, AU - Tripodo,Claudio, AU - Sartori,Enrico, AU - Cancila,Valeria, AU - Papaccio,Marta, AU - Castellani,Roberta, AU - Casola,Stefano, AU - Boniotti,Maria Beatrice, AU - Cavadini,Patrizia, AU - Lavazza,Antonio, Y1 - 2020/08/17/ PY - 2020/06/18/received PY - 2020/07/27/revised PY - 2020/07/28/accepted PY - 2020/8/21/pubmed PY - 2020/10/2/medline PY - 2020/8/21/entrez SP - 102951 EP - 102951 JF - EBioMedicine JO - EBioMedicine VL - 59 N2 - BACKGROUND: . The occurrence of trans-placental transmission of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection remains highly debated. Placental positivity for SARS-CoV-2 has been reported in selected cases, but infection or virus-associated disease of fetal tissues or newborns remains to be demonstrated. METHODS: We screened for SARS-CoV-2 spike (S) protein expression placentas from 101 women who delivered between February 7 and May 15, 2020, including 15 tested positive for SARS-CoV-2 RNA, 34 tested negative, and 52 not evaluated as they did not meet testing criteria (32), or delivered before COVID-19 pandemic declaration (20). Immunostain for SARS-CoV-2 nucleocapsid (N) was performed in the placentas of all COVID-19 positive women. One placenta resulted positive for the SARS-CoV-2 S and N proteins, which was further studied by RNA-in situ hybridization and RT-PCR for S transcripts, and by electron microscopy. A comprehensive immunohistochemical and immunofluorescence analysis of the placental inflammatory infiltrate completed the investigations. FINDINGS: SARS-CoV-2 S and N proteins were strongly expressed in the placenta of a COVID-19 pregnant woman whose newborn tested positive for viral RNA and developed COVID-19 pneumonia soon after birth. SARS-CoV-2 antigens, RNA and/or particles morphologically consistent with coronavirus were identified in villous syncytiotrophoblast, endothelial cells, fibroblasts, in maternal macrophages, and in Hofbauer cells and fetal intravascular mononuclear cells. The placenta intervillous inflammatory infiltrate consisted of neutrophils and monocyte-macrophages expressing activation markers. Absence of villitis was associated with an increase in the number of Hofbauer cells, which expressed PD-L1. Scattered neutrophil extracellular traps (NETs) were identified by immunofluorescence. INTERPRETATION: We provide first-time evidence for maternal-fetal transmission of SARS-CoV-2, likely propagated by circulating virus-infected fetal mononuclear cells. Placenta infection was associated with recruitment of maternal inflammatory cells in the intervillous space, without villitis. PD-L1 expression in syncytiotrophoblast and Hofbaeur cells, together with limited production of NETs, may have prevented immune cell-driven placental damage, ensuring sufficient maternal-fetus nutrient exchanges. SN - 2352-3964 UR - https://www.unboundmedicine.com/medline/citation/32818801/SARS_CoV2_vertical_transmission_with_adverse_effects_on_the_newborn_revealed_through_integrated_immunohistochemical_electron_microscopy_and_molecular_analyses_of_Placenta_ DB - PRIME DP - Unbound Medicine ER -