Term Human Placental Trophoblasts Express SARS-CoV-2 Entry Factors ACE2, TMPRSS2, and Furin

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a massive impact on human lives worldwide. While the airborne SARS-CoV-2 primarily affects the lungs, viremia is not uncommon. As placental trophoblasts are directly bathed in maternal blood, they are vulnerable to SARS-CoV-2. Intriguingly, the human fetus is largely spared from SARS-CoV-2 infection. We tested whether the human placenta expresses the main SARS-CoV-2 entry factors angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and furin and showed that ACE2 and TMPRSS2 are expressed in the trophoblast rather than in other placental villous cells. While furin is expressed in the main placental villous cell types, we surveyed, trophoblasts exhibit the highest expression. In line with the expression of these entry factors, we demonstrated that a SARS-CoV-2 pseudovirus could enter primary human trophoblasts. Mechanisms underlying placental defense against SARS-CoV-2 infection likely involve postentry processing, which may be germane for mitigating interventions against SARS-CoV-2. IMPORTANCE Pregnant women worldwide have been affected by COVID-19. As the virus is commonly spread to various organs via the bloodstream and because human placental trophoblasts are directly bathed in maternal blood, feto-placental infection by SARS-CoV-2 seems likely. However, despite the heightened risk to pregnant women, thus far the transmission risk of COVID-19 to the feto-placental unit seems extremely low. This has been recently attributed to a negligible expression of SARS-CoV-2 entry factors in the human placenta. We therefore sought to explore the expression of the entry factors ACE2 and TMPRSS2 in the different cell types of human placental villi. Using a combination of transcriptome sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), in situ hybridization, and immunofluorescence, we found that trophoblasts, but not the other main villous cell types, express ACE2 and TMPRSS2, with a broad expression of furin. Correspondingly, we also showed that primary human trophoblasts are permissive to entry of SARS-CoV-2 pseudovirus particles.

Infrequent Placental and Fetal Involvement in SARS-CoV-2 Infection: Pathology Data from a Large Medical Center

“…Recent study demonstrated the expression of the main SARS-CoV-2 cellular entry factors in villous trophoblast in term placentas, explaining why this cellular layer gets attacked by the virus [ 24 ]. The individual variability of these expression levels may be responsible for the different susceptibility to placental infection among women.…”

ACE2 Is Expressed in Immune Cells That Infiltrate the Placenta in Infection-Associated Preterm Birth

“…ACE2 is an active peptide of the renin–angiotensin system (RAS) which has been given considerable attention as a potential target for anti-viral therapeutics [ 6 ], since it is the main cell entry receptor of SARS-CoV-2 [ 7 ]. Other SARS-CoV-2 cell entry proteins have been described [ 8 ]. However, ACE2 is predominantly expressed in the syncytiotrophoblast layer (which directly faces the maternal blood), compared to other SARS-CoV-2 cell entry proteins [ 9 ].…”

Molecular Pathology Demonstration of SARS-CoV-2 in Cytotrophoblast from Placental Tissue with Chronic Histiocytic Intervillositis, Trophoblast Necrosis and COVID-19

“…Based upon the observations made in recent articles describing the pathology findings from infected placentas, it can be confidently stated that the syncytiotrophoblast is the most frequent cell type composing the maternal-fetal interface to be infected with SARS-CoV-2 [28]. The syncytiotrophoblast expresses the major cell surface receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), throughout gestation [43,44]. Because of its strategic location on the surface of the syncytiotrophoblast, this receptor is exposed directly to maternal blood that circulates through the intervillous space, and which may contain SARS-CoV-2 in infected pregnant women with viremia.…”

“…Because of its strategic location on the surface of the syncytiotrophoblast, this receptor is exposed directly to maternal blood that circulates through the intervillous space, and which may contain SARS-CoV-2 in infected pregnant women with viremia. In addition to ACE2, the syncytiotrophoblast also expresses the SARS-CoV-2 entry factors transmembrane protease serine 2 (TMPRSS2), and furin [44,45]. Recent evidence has suggested that in contrast to 1st and 2nd trimester placentas, there is low expression of the ACE2 viral receptor on placental trophoblast cells during the later stages of pregnancy [46,47], potentially accounting for the relatively low rate of transplacental transmission that occurs with SARS-CoV-2.…”