SARS-CoV-2 modulates virus receptor expression in placenta and can induce trophoblast fusion, inflammation and endothelial permeability

Abstract

SARS-CoV-2 is a devastating virus that induces a range of immunopathological mechanisms including cytokine storm, apoptosis, inflammation and complement and coagulation pathway hyperactivation. However, how the infection impacts pregnant mothers is still being worked out due to evidence of vertical transmission of the SARS-CoV-2, and higher incidence of pre-eclampsia, preterm birth, caesarian section, and fetal mortality. In this study, we assessed the levels of the three main receptors of SARS-CoV-2 (ACE2, TMPRSS2 and CD147) in placentae derived from SARS-CoV-2 positive and negative mothers. Moreover, we measured the effects of Spike protein on placental cell lines, in addition to their susceptibility to infection. SARS-CoV-2 negative placentae showed elevated levels of CD147 and considerably low amount of TMPRSS2, making them non-permissive to infection. SARS-CoV-2 presence upregulated TMPRSS2 expression in syncytiotrophoblast and cytotrophoblast cells, thereby rendering them amenable to infection. The non-permissiveness of placental cells can be due to their less fusogenicity due to infection. We also found that Spike protein was capable of inducing pro-inflammatory cytokine production, syncytiotrophoblast apoptosis and increased vascular permeability. These events can elicit pre-eclampsia-like syndrome that marks a high percentage of pregnancies when mothers are infected with SARS-CoV-2. Our study raises important points relevant to SARS-CoV-2 mediated adverse pregnancy outcomes.

Evidence of Placental Villous Inflammation and Apoptosis in Third-Trimester Symptomatic SARS-CoV-2 Maternal Infection

“…Other studies also showed an increase in COVID-19-infected placental apoptosis, although indirectly, including an increase of proapoptotic Bax protein 27 and Caspase 3/7 induction in the infected placental cell line. 23 In particular, interferon-γ, which was elevated in this study, is known to induce trophoblast apoptosis, 28 which also occurs in other clinical circumstances, including preeclampsia and toxoplasma infection. 25 29 …”

“… 20 21 22 Our observation revealed that the trophoblast villous cells expressed both ACE-2 and a significantly higher amount of TMPRSS2 in the COVID-19 group, which has also been reported in previous studies. 10 23 24 This protease increment showed facilitation and active priming in host cells, which will be an important factor in the entry of viral infections. 19 23 Lower levels of ACE2 protein in placentas from COVID-19-positive pregnancies have also been reported in a previous study, hinting that SARS-CoV-2 infection and inflammation may directly or indirectly downregulate ACE2 expression as a result of active shedding.…”

“… 10 23 24 This protease increment showed facilitation and active priming in host cells, which will be an important factor in the entry of viral infections. 19 23 Lower levels of ACE2 protein in placentas from COVID-19-positive pregnancies have also been reported in a previous study, hinting that SARS-CoV-2 infection and inflammation may directly or indirectly downregulate ACE2 expression as a result of active shedding. 20 …”

“… 25 One of the causes of this high cytokine production, which is likely to have limited the movement of the virus, can be the migration of immune cells including macrophages, T cells, and NK cells obtained in the COVID-19-infected placenta. 24 26 The analysis of placental RNA 24 and the COVID-19-infected cell line 23 also revealed significant levels of inflammatory and anti-inflammatory cytokines, including IL-6, which was also shown to be elevated in trophoblast. 27 …”

Impact of COVID-19 on pregnant women's health: Consequences in obstetrics two years after the pandemic

“…Numerous studies suggest that ACE-2 and TMPRSS2 expression is negligible in first, second, and third trimester placental cells ( Gengler et al, 2021 , Pique-Regi et al, 2020 ). However, SARS-CoV-2 infection may be associated with vascular injury in pregnant women, in whom ischemic damage to the placenta may facilitate viral cell entry ( Agostinis et al, 2022 , Edlow et al, 2020 ). There may also be other cellular mediators that may be responsible for cell entry such as cathepsin L, FURIN, and sialic acid-binding Ig-like lectin 1 ( Pique-Regi et al, 2020 ).…”