SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system

• Published in: Med (New York, N.Y. : Online) Vol. 2; no. 5; pp. 575 - 590.e5
• Main Authors: Verma, Sonam, Joshi, Chetanchandra S., Silverstein, Rachel B., He, Mai, Carter, Ebony B., Mysorekar, Indira U.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2021
• Subjects: ACE2; Angiotensin-Converting Enzyme 2; AT1-AA; AT1R; Clinical and Translational; COVID-19; decidua; extravillous trophoblasts; Female; Humans; placenta; Placenta - metabolism; Placenta Growth Factor - metabolism; PlGF; pre-eclampsia; Pre-Eclampsia - metabolism; Pregnancy; Pregnancy Complications, Infectious - metabolism; Renin-Angiotensin System; SARS-CoV-2; sFlt1; Spike Glycoprotein, Coronavirus - metabolism; Vascular Endothelial Growth Factor Receptor-1 - metabolism; sFlt1; ACE2; extravillous trophoblasts; decidua; pregnancy; placenta; AT1R; pre-eclampsia; Translation to patients; PlGF; AT1-AA
• ISSN: 2666-6340; 2666-6359; 2666-6340
• DOI: 10.1016/j.medj.2021.04.009

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to increase the risk of adverse pregnancy outcomes, such as pre-eclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear. We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta, which controls blood pressure, we treated human trophoblasts with recombinant spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing spike protein (VSV-S). Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing angiotensin-converting enzyme 2 (ACE2) and demonstrate that infected placentas had significantly reduced ACE2. In response to both spike protein and VSV-S, cellular ACE2 decreased although angiotensin II receptor type 1 (AT1R) increased with concomitant increase in soluble fms-like tyrosine kinase-1 (sFlt1). Viral infection decreased pro-angiogenic factors, AT2R, and placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and angiotensin II type 1-receptor autoantibodies prior to delivery, both signatory markers of pre-eclampsia. SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes, such as pre-eclampsia in pregnant women. NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement). [Display omitted] SARS-CoV-2 colonizes multiple compartments at the maternal-fetal interfacePlacental ACE2 expression decreases with SARS-CoV-2 infectionSARS-CoV-2 infection leads to dysregulation of placental renin-angiotensin systemSARS-CoV-2 infection is associated with markers of hypertensive disorders of pregnancy SARS-CoV-2 infection appears to increase the risk of pre-eclampsia, a dangerous condition in pregnancy characterized by high blood pressure. However, the mechanisms by which it may do so are currently unknown. Researchers at the Washington University School of Medicine in St. Louis, Missouri show that SARS-CoV-2 colonizes multiple cell types in the human placenta. In addition, infection is associated with alterations in the placental renin-angiotensin hormonal system, which regulates blood pressure leading to increased markers of pre-eclampsia. This study provides insights into the pathology of SARS-CoV-2 infection in the placenta and supports a link between SARS-CoV-2 infection and development of pre-eclampsia in pregnant women through changes in the renin-angiotensin system. Verma et. al. show that the novel coronavirus, SARS-CoV-2, infects maternal and fetal cells in the human placenta, and infection is associated with decreased angiotensin-converting enzyme 2 (ACE2) expression and alterations in the blood-pressure-regulating renin angiotensin system (RAS). Alterations in this system are implicated in hypertensive disorders of pregnancy, such as pre-eclampsia. These findings shed light on how SARS-CoV-2 infection may increase risk of adverse pregnancy outcomes.