Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with robust inflammatory response at the maternal-fetal interface

Summary Background Pregnant women are at increased risk for severe outcomes from COVID-19, but the pathophysiology underlying this increased morbidity and its potential impact on the developing fetus is not well understood. Methods We assessed placental histology, ACE2 expression, and viral and immune dynamics at the term placenta in pregnant women with and without respiratory SARS-CoV-2 infection. Findings The majority (13/15) of placenta analyzed had no detectable viral RNA in the placenta. ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term, suggesting that low ACE2 expression may protect the term placenta from viral infection. Using immortalized cell lines and primary isolated placental cells, and find that cytotrophoblasts, the trophoblast stem cell and precursor to syncytiotrophoblasts, rather than syncytiotrophoblasts or Hofbauer cells, are most vulnerable to SARS-CoV-2 infection in vitro. To better understand potential immune mechanisms shielding placental cells from infection in vivo, we performed bulk and single cell transcriptomic analyses, and found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited robust immune responses, including increased activation of NK and T cells and increased expression of interferon-related genes, as well as markers associated with pregnancy complications, such as preeclampsia. Conclusions SARS-CoV-2 infection in late pregnancy is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion. Funding NIH (T32GM007205, F30HD093350, K23MH118999, R01AI157488, U01DA040588), and Fast Grant funding support from the Emergent Ventures at the Mercatus Center.