Is SARS-CoV-2 infection a risk factor for early pregnancy loss? ACE2 and TMPRSS2 co-expression and persistent replicative infection in primitive trophoblast.

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.