A Message from the Human Placenta: Structural and Immunomodulatory Defense against SARS-CoV-2

Abstract

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical and structural defense against viral infections. We further discuss the potential molecular mechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulated placental immune defense and modulation strategies. Particularly, immunomodulatory mechanisms employed by the placenta may mitigate violent immune response, maybe soften cytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission.

Pregnancy and COVID-19

“…Further research is required, including standardized examination of placental samples from women with SARS-CoV-2 and matched negative controls, by pathologists unaware of SARS-CoV-2 status, to verify these preliminary reports of potential vascular and thrombotic effects in the placenta associated with maternal COVID-19. In addition, these findings should be correlated to clinical status of the fetus, ideally with longer-term follow-up ( 66 ).…”

“…Given the lack of ACE2 and TMPRSS2 coexpression in the placenta, it, therefore, seems likely that SARS-CoV-2 enters the placental tissues via an alternative mechanism ( 66 , 102 ). A number of other proteases have also been implicated.…”

Placental Pathology of COVID-19 with and without Fetal and Neonatal Infection: Trophoblast Necrosis and Chronic Histiocytic Intervillositis as Risk Factors for Transplacental Transmission of SARS-CoV-2

“…Enhancing its role as the key cellular layer of the intrinsic defense system of the placenta, syncytiotrophoblast is periodically regenerated, does not contain periodic gap junctions, and has a uniquely dense cytoskeletal network that provides a protective brush border at the apical surface. In addition, cytotrophoblast cells can also play a defensive role, and the basement membrane zone lying beneath these cells also form an additional physical barrier [47][48][49][50].…”

Human Placenta Exosomes: Biogenesis, Isolation, Composition, and Prospects for Use in Diagnostics

“…Given the COVID-19 pandemic, it is of interest to study trophoblast-derived exosomes’ antiviral activity against SARS-CoV-2 coronavirus since these exosomes are known to have antiviral activity [ 71 , 89 , 90 ]. Currently, it is known that the virus enters the human placenta: not only RNA of the virus is detected in the placenta [ 91 ], but also virions [ 92 ], while most newborns are healthy [ 93 ].…”