SARS-CoV-2 Infects Syncytiotrophoblast and Activates Inflammatory Responses in the Placenta

Abstract

SARS-CoV-2 infection during pregnancy leads to an increased risk of adverse pregnancy outcomes. Although the placenta itself can be a target of virus infection, most neonates are virus free and are born healthy or recover quickly. Here, we investigated the impact of SARS-CoV-2 infection on the placenta from a cohort of women who were infected late during pregnancy and had tested positive for SARS-CoV-2 by qRT-PCR at delivery. SARS-CoV-2 genomic and subgenomic RNA was detected in 23 out of 55 placentas (41%). Three placentas with high virus content were obtained from mothers who presented with severe COVID-19 and whose pregnancies resulted in adverse outcomes for the fetuses, including intrauterine fetal demise, stillbirth, and a preterm delivered baby still in newborn intensive care. Examination of the placental samples with high virus content showed efficient SARS-CoV-2 infection, using RNA in situ hybridization to detect genomic and replicating viral RNA, and immunohistochemistry to detect SARS-CoV-2 nucleocapsid protein. Infection was restricted to syncytiotrophoblast cells that envelope the fetal chorionic villi and are in direct contact with maternal blood. The infected placentas displayed massive infiltration of maternal immune cells including macrophages into intervillous spaces, potentially contributing to inflammation of the tissue. Ex vivo infection of placental cultures with SARS-CoV-2 or with SARS-CoV-2 spike (S) protein pseudotyped lentivirus targeted mostly syncytiotrophoblast and, to a lesser extent, endothelial cells. Infection was reduced by using blocking antibodies against ACE2 and against Neuropilin 1, suggesting that SARS-CoV-2 may utilize alternative receptors for entry into placental cells.

Diffuse and Localized SARS-CoV-2 Placentitis

“…We reviewed the literature and identified 56 previously published and well-documented cases of diffuse SARS-CoV-2 placentitis 6,7,14–26. A summary of the pregnancy-related features of these, together with our 4 new cases, is provided in Table 2.…”

COVID-19 in pregnancy: implications for fetal brain development

“…Immune activation at the maternal-fetal interface and in fetal cord blood has been observed in prenatal SARS-CoV-2 infection Although the immune and inflammatory response to SARS-CoV-2 in pregnancy is only beginning to be characterized, early data show a proinflammatory cytokine phenotype in pregnant women with active SARS-CoV-2, with interferon-gamma (IFN-γ), IL-1β, and IL-6 most implicated, particularly in cases of severe COVID-19 disease [77,78]. Several studies have demonstrated the potential for maternal SARS-CoV-2 infection to stimulate an intense placental immune and inflammatory response [79][80][81], both in the presence (rare) [81] and absence (more common) [80,82,83] of direct SARS-CoV-2 infection of the placenta. Substantial infiltration of maternal immune cells into the placenta has been observed in cases of severe maternal COVID-19 disease, adverse neonatal outcomes, and heavy placental SARS-CoV-2 viral burden [81].…”

“…Several studies have demonstrated the potential for maternal SARS-CoV-2 infection to stimulate an intense placental immune and inflammatory response [79][80][81], both in the presence (rare) [81] and absence (more common) [80,82,83] of direct SARS-CoV-2 infection of the placenta. Substantial infiltration of maternal immune cells into the placenta has been observed in cases of severe maternal COVID-19 disease, adverse neonatal outcomes, and heavy placental SARS-CoV-2 viral burden [81]. In addition, maternal SARS-CoV-2 infection is associated with hyperplasia and/or increased density of fetal placental macrophages or Hofbauer cells, typically in the absence of Hofbauer cell infection [80,84].…”

Maternal COVID-19 Vaccination and Its Potential Impact on Fetal and Neonatal Development

“…ACE2 is also expressed within placental tissues [52], and is involved in regulating fetal myocardial growth and lung and brain development [53]. A recent pre-print study showed that blocking ACE2 with an anti-ACE2 antibody reduced placental SARS-CoV-2 infection [54]. This is one of a number of studies that have demonstrated that the placenta is susceptible to SARS-CoV-2 [53,55], and may also be responsive to spike proteins, which have been identified at low concentrations in plasma from recipients of the Moderna vaccine [56].…”