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

• Published in: Med (New York, N.Y. : Online) Vol. 2; no. 5; pp. 591 - 610.e10
• Main Authors: Lu-Culligan, Alice, Chavan, Arun R., Vijayakumar, Pavithra, Irshaid, Lina, Courchaine, Edward M., Milano, Kristin M., Tang, Zhonghua, Pope, Scott D., Song, Eric, Vogels, Chantal B.F., Lu-Culligan, William J., Campbell, Katherine H., Casanovas-Massana, Arnau, Bermejo, Santos, Toothaker, Jessica M., Lee, Hannah J., Liu, Feimei, Schulz, Wade, Fournier, John, Muenker, M. Catherine, Moore, Adam J., Konnikova, Liza, Neugebauer, Karla M., Ring, Aaron, Grubaugh, Nathan D., Ko, Albert I., Morotti, Raffaella, Guller, Seth, Kliman, Harvey J., Iwasaki, Akiko, Farhadian, Shelli F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2021
• Subjects: Angiotensin-Converting Enzyme 2 - genetics; Clinical and Translational; COVID-19; Female; Humans; placenta; Placenta - metabolism; Pregnancy; Pregnancy Complications, Infectious - metabolism; SARS-CoV-2; COVID-19; placenta; SARS-CoV-2; Translation to patients; pregnancy
• ISSN: 2666-6340; 2666-6359; 2666-6340
• DOI: 10.1016/j.medj.2021.04.016

Pregnant women are at increased risk for severe outcomes from coronavirus disease 2019 (COVID-19), but the pathophysiology underlying this increased morbidity and its potential effect on the developing fetus is not well understood. We assessed placental histology, ACE2 expression, and viral and immune dynamics at the term placenta in pregnant women with and without respiratory severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The majority (13 of 15) of placentas analyzed had no detectable viral RNA. 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, we found that cytotrophoblasts, the trophoblast stem cells and precursors 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 transcriptomics analyses and found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited robust immune responses, including increased activation of natural killer (NK) and T cells, increased expression of interferon-related genes, as well as markers associated with pregnancy complications such as preeclampsia. 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. NIH (T32GM007205, F30HD093350, K23MH118999, R01AI157488, U01DA040588) and Fast Grant funding support from Emergent Ventures at the Mercatus Center. [Display omitted] Most women with SARS-CoV-2 at delivery had no detectable viral RNA at the placentaACE2 is highly expressed in the placenta during early pregnancy but rarely at termPlacental cytotrophoblasts are susceptible to SARS-CoV-2 infection in vitroRNA-seq reveals robust placental immune activation during maternal SARS-CoV-2 infection Pregnant women with COVID-19 are at increased risk for severe illness and pregnancy complications compared with non-pregnant women. Researchers at Yale School of Medicine analyzed placentas from SARS-CoV-2-infected women at the time of delivery and found that, although placental cells are susceptible to infection in vitro, viral RNA is rarely detected in clinical samples. The Yale team observed local immune responses at the maternal-fetal interface, including upregulation of interferon pathways and activation of T and NK cells. Although placental immune activation during maternal SARS-CoV-2 infection likely represents a host defense mechanism of shielding the maternal-fetal interface from infection, these inflammatory changes may contribute to the increased risk for complications seen in COVID-19-affected pregnancies. COVID-19 is more severe in pregnant women and can lead to adverse fetal outcomes. Through histological and gene expression studies of placentas from infected women, Lu-Culligan et al. find that maternal SARS-CoV-2 infection during term pregnancy and delivery is associated with immune activation at the maternal-fetal interface even in the absence of detectable virus in the placenta.