Is SARS-CoV-2 Infection a Risk Factor for Early Pregnancy Loss? ACE2 and TMPRSS2 Coexpression and Persistent Replicative Infection in Primitive Trophoblast

Abstract

Background SARS-CoV-2 infection in term placenta is relatively rare. However, growing evidence suggests that susceptibility of the human placenta to infection may vary by gestational age and pathogen. For several viral infections, susceptibility appears to be greatest during early gestation. Infections of the peri-implantation placenta that result in pre-clinical pregnancy loss would typically go undetected. Little is known about the effects of SARS-CoV-2 on the peri-implantation human placenta since this time in pregnancy can only be modeled in vitro. Methods We used a human embryonic stem cell-derived model of peri-implantation placental development to assess patterns of ACE2 and TMPRSS2 transcription and protein expression in primitive trophoblast. These molecules are involved in SARS-CoV-2 cell entry and infection. We then infected the same trophoblast cell model with a clinical isolate of SARS-CoV-2, and documented infection dynamics. Results ACE2 and TMPRSS2 were transcribed and translated in stem-cell derived trophoblast, with preferential expression in syncytialized cells. These same syncytialized cells supported replicative and persistent infection by SARS-CoV-2, while non-syncytialized trophoblast cells in the same cultures did not. Conclusions Co-expression of ACE2 and TMPRSS2 in early human embryonic stem cell-derived trophoblast and the robust and replicative infection limited to syncytiotrophoblast equivalents support the hypothesis that increased viral susceptibility may be a defining characteristic of primitive trophoblast. Potential implications of these findings for early pregnancy loss deserve further investigation.

The immune checkpoint molecule, VTCN1/B7-H4, guides differentiation and suppresses proinflammatory responses and MHC class I expression in an embryonic stem cell-derived model of human trophoblast

“…Unlike TB derived from term placenta, BAP-generated primitive TB of the early first trimester has diminished levels of 1) interferon-stimulated genes (ISG), such as ISG15 , MX1 , DDX58 ( RIG- 1), 2) interferon induced proteins with tetratricopeptide repeats ( IFIT ) family members, 3) and oligoadenylate synthase-like ( OAS ) family members, all of which augment the innate immune response to viral infection ( 44 , 45 ). Such diminished responses have been linked to a greater risk of vertical transmission of viruses in early gestation including transmission of CMV, HSV, Zika virus and SARS-CoV-2 ( 46 – 50 ). Our RNA-seq analysis revealed that expression of several ISGs were upregulated when VTCN1 expression was repressed ( Figure 3A ).…”

Causes and Effects of COVID-19 Vaccine Hesitancy Among Pregnant Women and its Association with Adverse Maternal, Placental, and Perinatal Outcomes

“…COVID-19 vaccination in pregnancy is a severe health concern given the increased maternal mortality and severe disease possible with COVID-19 infection in pregnancy [1,2,66,67]. Evidence of vaccination hesitancy in pregnancy can be observed in the study by Germann et al who conducted a multivariate Poisson regression analysis to estimate vaccination by baseline vaccination hesitancy status.…”

The Multi-faceted Effects of COVID-19 on Female Reproductive Health: An Updated Narrative Review

“…While TMPRSS2 expression begins later in blastocysts, primarily in the trophectoderm, ACE2 first occurs in embryos early [99]. Strong ACE2/TMPRSS2 co-expression in day 6 peri-implantation embryos indicates susceptibility [100]. Day 5-7 blastocysts containing ACE2/BSG are indicative of SARS-CoV-2 susceptibility.…”