Expression of SARS-CoV-2 cell entry genes, ACE2 and TMPRSS2, in the placenta across gestation and at the maternal-fetal interface in pregnancies complicated by preterm birth or preeclampsia

Bloise, Enrrico; Zhang, Jianhong; Nakpu, Jittanan; Hamada, Hirotaka; Dunk, Caroline E.; Li, Siliang; Imperio, Guinever E.; Nadeem, Lubna; Kibschull, Mark; Lye, Phetcharawan; Matthews, Stephen G.; Lye, Stephen J.

Abstract Background While there is some evidence that SARS-CoV-2 can invade the human placenta, limited data exist on the gestational-age dependent expression profile of the SARS-CoV-2 cell entry mediators, ACE2 and TMPRSS2 at the human maternal-fetal interface. There is also no information as to whether the expression of these mediators is altered in pregnancies complicated by pre-eclampsia (PE) or preterm birth (PTB). This is important since the expression of decidual and placental ACE2 and TMPRSS2 across gestation may impact susceptibility of pregnancies to vertical transmission of SARS-CoV-2. Objectives To investigate the expression pattern of specific SARS-CoV-2 cell entry genes, ACE2 and TMPRSS2, in the placenta across human pregnancy and in paired samples of decidua and placenta in pregnancies complicated by PTB or PE compared to term, uncomplicated pregnancies. Study Design Two separate cohorts of patients, totalling 87 pregnancies were included. The first cohort comprised of placentae from first (7-9 weeks), second (16-18 weeks), third-trimester preterm (26-31 weeks) and third-trimester term (38-41 weeks) pregnancies (n=5/group), whereas, the second independent cohort, included matched decidua and placentae from pregnancies from term, uncomplicated pregnancies (37-41 weeks; n=14) as well as pregnancies complicated by PTB (26-37 weeks, n=11) or PE (25-37 weeks n=42). Samples were subjected to qPCR and next-generation sequencing (NGS)/RNAseq for ACE2 and TMPRSS2 mRNA expression quantification, respectively. Results In the first cohort, the SARS-CoV-2 cell entry genes ACE2 and TMPRSS2 exhibited a gestational-age dependent expression profile, i.e. ACE2 and TMPRSS2 mRNA was higher (p<0.05) in the first trimester compared to second trimester, PTB and term placentae (p<0.05) and exhibited a negative correlation with gestational age (p<0.05). In the second cohort, RNAseq demonstrated very low/undetectable expression levels of ACE2 in PTB, PE and term decidua and in placentae from late gestation. In contrast, TMPRSS2 was expressed in both decidual and placental samples but did not change in pregnancies complicated by either PTB or PE. Conclusions The increased expression of these SARS-CoV-2 cell entry associated genes in the placenta during the first trimester compared to later stages of pregnancy suggest the possibility of differential susceptibility to placental entry to SARS-CoV-2 across pregnancy. Even though there is some evidence of increased rates of PTB associated with SARS-CoV-2 infection, we found no increase in mRNA expression of ACE2 or TMPRSS2 at the maternal-fetal interface.