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

Abstract

COVID-19 is associated with increased incidence of preterm birth (PTB). We assessed pathways by which SARS-CoV-2 could access the placenta. Placentae, from PTB with or without chorioamnionitis (ChA), or from term pregnancies (n = 12/13/group) were collected. Peripheral blood was collected from healthy pregnant women (n = 6). Second trimester placental explants (16–20 weeks, n = 5/group) were treated with lipopolysaccharide (LPS, to mimic bacterial infection) and ACE2, CCL2, IL-6/8 and TNFα mRNA was assessed. ChA-placentae exhibited increased ACE2 and CCL2 mRNA expression (p < 0.05). LPS increased cytokine and ACE2 mRNA in placental explants. Placental ACE2 protein localized to syncytiotrophoblast, fetal endothelium, extravillous trophoblast and in immune cells-subsets (M1/M2 macrophage and neutrophils) within the villous stroma. Significantly increased numbers of M1 macrophage and neutrophils were present in the ChA-placenta (p < 0.001). Subsets of peripheral immune cells from pregnant women express the ACE2 mRNA and protein. A greater fraction of granulocytes was positive for ACE2 protein expression compared to lymphocytes or monocytes. These data suggest that in pregnancies complicated by ChA, ACE2 positive immune cells in the maternal circulation have the potential to traffic SARS-CoV-2 virus to the placenta and increase the risk of vertical transmission to the placenta/fetus.

Effects of Vertical Transmission of Respiratory Viruses to the Offspring

“…SARS-CoV-2 functional modulation of macrophages localized on chorioamniotic membranes has also been reported, resulting in a mild inflammatory response systemically and at the maternal-fetal interface mediated by IL-8, IL-10, and IL-15 ( 92 ). Accordingly, histopathologic findings of abnormal maternal or fetal vascular perfusion were detected in 46% and 35% of analyzed placentas, respectively ( 86 – 91 ). Thus, the virus can cause vascular injury leading to ischemic damage of the placenta, affecting the fetus even without a direct infection ( 86 – 91 ).…”

“…Looking more specifically to the maternal-fetal interface, studies using precision-cut slices (PCSs) have shown that SARS-CoV-2 infection of the human placenta results in complete replication cycles with the release of infectious virus (84). Interestingly, the placenta's susceptibility to SARS-CoV-2 replication was related to the expression of ACE2 and TMPRSS2 (84)(85)(86)(87)(88)(89)(90)(91). A recent study also showed that ACE2-positive circulating immune cells of pregnant women with COVID-19 and chorioamnionitis could transfer the SARS-CoV-2 virus to the placenta, thus increasing the chance of vertical transmission (91).…”

“…Interestingly, the placenta's susceptibility to SARS-CoV-2 replication was related to the expression of ACE2 and TMPRSS2 (84)(85)(86)(87)(88)(89)(90)(91). A recent study also showed that ACE2-positive circulating immune cells of pregnant women with COVID-19 and chorioamnionitis could transfer the SARS-CoV-2 virus to the placenta, thus increasing the chance of vertical transmission (91). Several other investigators examined samples from midtrimester placentae of women with COVID-19.…”

“…However, whether SARS-CoV-2 isolation was due to primary infection or secondary to other placental pathology remains unclear. Importantly, when virus-like particles were detected in placental tissues, fetal tissues did not always show SARS-CoV-2 expression (84,(86)(87)(88)(89)(90)(91). Other authors reported that exposure to SARS-CoV-2 causes neither cytotoxicity nor a proinflammatory cytokine response, and a significant expression in type-III IFN was also noted.…”

COVID‐19 and vertical transmission: assessing the expression of ACE2/TMPRSS2 in the human fetus and placenta to assess the risk of SARS‐CoV‐2 infection

“…14 Infection via trafficked maternal cells has been suggested, as evidenced by an observed expression of ACE2 protein in infiltrating maternal cells in human placentas with chorioamnionitis. 15 However, it is of note that despite widely reported placental pathology in viraemic mothers, infection in the fetus has not been well characterised and does not seem to be a common feature of preterm birth in association with a confirmed infection in the mother. 16 Neonatal infection plausibly could occur either through an ascending infection through the vagina and cervical canal or during vaginal birth via direct infant contact with maternal virus.…”