Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface.
Alice Lu-Culligan, Arun R Chavan, Pavithra Vijayakumar, Lina Irshaid, Edward M Courchaine, Kristin M Milano, Zhonghua Tang, Scott D Pope, Eric Song, Chantal B F Vogels, William J Lu-Culligan, Katherine H Campbell, Arnau Casanovas-Massana, Santos Bermejo, Jessica M Toothaker, Hannah J Lee, Feimei Liu, Wade Schulz, John Fournier, M Catherine Muenker, Adam J Moore, Yale IMPACT Team, Liza Konnikova, Karla M Neugebauer, Aaron Ring, Nathan D Grubaugh, Albert I Ko, Raffaella Morotti, Seth Guller, Harvey J Kliman, Akiko Iwasaki, Shelli F Farhadian
Author Information
Alice Lu-Culligan: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Arun R Chavan: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Pavithra Vijayakumar: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Lina Irshaid: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
Edward M Courchaine: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
Kristin M Milano: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Zhonghua Tang: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Scott D Pope: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Eric Song: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Chantal B F Vogels: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
William J Lu-Culligan: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
Katherine H Campbell: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Arnau Casanovas-Massana: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
Santos Bermejo: Section of Pulmonary and Critical Care Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
Jessica M Toothaker: Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.
Hannah J Lee: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Feimei Liu: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Wade Schulz: Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
John Fournier: Section of Infectious Diseases, Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
M Catherine Muenker: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
Adam J Moore: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
Liza Konnikova: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Karla M Neugebauer: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
Aaron Ring: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Nathan D Grubaugh: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
Albert I Ko: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
Raffaella Morotti: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
Seth Guller: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Harvey J Kliman: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Akiko Iwasaki: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Shelli F Farhadian: Section of Infectious Diseases, Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
BACKGROUND: 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. METHODS: 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. FINDINGS: 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 . To better understand potential immune mechanisms shielding placental cells from infection , 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. 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 Emergent Ventures at the Mercatus Center.
