SARS-CoV-2 cell entry gene ACE2 expression in immune cells that infiltrate the placenta in infection-associated preterm birth

Abstract

COVID-19 infection during pregnancy is associated with an increased incidence of preterm birth but neonatal infection is rare. We assessed pathways by which SARS-CoV-2 could access the placenta and contribute to fetal transmission. Placentas from pregnancies complicated with chorioamnionitis (ChA), exhibited increased expression of ACE2 mRNA. Treatment of 2nd trimester placental explants with LPS, induced an acute increase in cytokine expression followed by ACE2 mRNA. Placental ACE2 protein localized to syncytiotrophoblast, in fetal blood vessels and M1/M2 macrophage and neutrophils within the villous stroma. Increased numbers of M1 macrophage and neutrophils were present in the placenta of ChA pregnancies. Maternal peripheral immune cells (mainly granulocytes and monocytes) express the ACE2 mRNA and protein. These data suggest that in COVID19 positive pregnancies complicated by ChA, ACE2 positive immune cells have the potential to traffic SARS-CoV-2 virus to the placenta and increase the risk of vertical transmission to the placenta/fetus.

Intrauterine vertical SARS‐CoV‐2 infection: a case confirming transplacental transmission followed by divergence of the viral genome

“…21 Other studies have suggested that placental inflammation may play a central role in the transmission of SARS-CoV-2. Lye et al 22 reported that ACE2 expression was increased in placentas that experienced chorioamnionitis. The authors proposed the possibility of vertical transmission by way of SARS-CoV-2-carrying immune cells infiltrating placentas complicated with chorioamnionitis.…”

Comprehensive analysis of COVID-19 during pregnancy

“…In a pre-print, Lye et al. reported that ACE2 expression was increased in placentas that experienced inflammation as a result of intrauterine bacterial infection, known as chorioamnionitis [ 50 ]. Treatment of placental explants with LPS resulted in enhanced ACE2 expression ex vivo .…”

Role of ACE2 in pregnancy and potential implications for COVID-19 susceptibility

“…Placentas from COVID-19 positive mothers also show higher fibrin deposition, signs of inflammation and lesions consistent with maternal and fetal vascular malperfusion, independent of evidence of vertical transmission [22,43,44]. Furthermore, placental intervillous inflammatory infiltrate from COVID-19 patients presents neutrophils, monocytes and macrophages expressing activation markers [45]. Taken together, these findings underline a transmission susceptibility, even though the mechanisms are still unclear and certainly not manifested in all COVID-19 positive pregnancies.…”

“…Alternative entry routes for SARS-CoV-2 independent of TMPRSS2 priming are emerging and also may be considered for placental infection [23,45,46]. Cathepsin L and furin are largely expressed in placentas at all gestational ages.…”

“…Furthermore, a large number of different immune cells infiltrate the feto-maternal interface while exerting key roles in placentation and during labor [45]. Placentas naturally present a high content of maternal and fetal macrophages (Figure 2) [47], and maternal peripheral immune cells also express ACE2 [45].…”