SARS-CoV-2 delta and omicron variants alter trophoblast cell fusion and syncytiotrophoblast dynamics : new insights into placental vulnerability

Article Article scientifique Article SARS-CoV-2 delta and omicron variants alter trophoblast cell fusion and syncytiotrophoblast dynamics : new insights into placental vulnerability eng 2025-10-07 author Essaidi-Laziosi Manel 0000-0003-1643-4965 Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 682799 Département de médecine (DEMED) author Alvarez Catia Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 778118 author Yaron Michal 0000-0003-0665-4710 Service of Gynecology, Department of Woman, Child and Adolescent, Geneva University Hospitals, Geneva, Switzerland.,Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 668428 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) author Sattonnet Pascale Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 813845 Pascale Sattonnet-Roche author Adea Kenneth Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 631795 author Cornut Matthey-Doret Mélanie Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 643671 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) author Wuillemin Christine Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 687158 author Bekliz Meriem Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 952376 author Sarmiento Yoann Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 861189 author Gibson Chloé Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 418623 author Kaiser Laurent Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. 28229 Département de médecine (DEMED) author Rougemont-Pidoux Anne-Laure 0000-0002-1785-792X Pediatric and Fetoplacental Pathology Unit, Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland. 29140 Département de pathologie et immunologie (PATIM) author Eckerle Isabella Anne 0000-0002-4850-7172 Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. isabella.eckerle@unige.ch.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. isabella.eckerle@unige.ch. 894639 Département de médecine (DEMED) author Cohen Marie-Benoîte 0000-0003-4621-5464 Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland. marie.cohen@unige.ch. 135615 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) 718 10.1038/s41419-025-08016-x 41057296 2041-4889 PMC12504560 https://www.nature.com/articles/s41419-025-08016-x Pregnancy is associated with an increased risk of severe COVID-19. In addition, SARS-CoV-2 infection during gestation has been linked to adverse obstetrical outcomes and placental abnormalities. Nevertheless, the susceptibility of early trophoblast cells to SARS-CoV-2 and the potential consequences of infection on trophoblast function remain unclear. In this study, we assessed the permissiveness of first trimester trophoblast cells to SARS-CoV-2 infection and its impact on trophoblast cells fusion. To address this, we isolated primary cytotrophoblast (CTB) cells from first trimester human placentas and allow their differentiation into STB in vitro. These cells were infected with SARS-CoV-2 variants of concern, including Delta and Omicron (BA.1, BA.2, BA.5). Viral replication was assessed by RT-qPCR and immunofluorescence, while host cell responses, including expression of viral entry receptors and innate immunity genes, were measured by RT-qPCR. Trophoblast fusion was evaluated by staining and calculating the fusion index. In parallel, placental tissues from SARS-CoV-2-infected pregnancies were analyzed by immunohistochemistry to quantify syncytial knots (SK) formation in vivo. Our results demonstrate that both first trimester CTB and STB are permissive to SARS-CoV-2 infection in a variant- and donor-dependent manners, with Delta exhibiting higher replication efficiency compared to Omicron variants. In STB, viral replication did not correlate with the induction of entry receptors or type III interferon responses. However, in CTB, viral replication was significantly associated with enhanced cell fusion. In parallel, an increased number of SK was observed in infected placental areas in vivo compared to non-infected regions from the same placenta and to gestational age-matched controls. Altogether, these in vitro and in vivo results suggest that SARS-CoV-2 infection in early pregnancy may alter STB turnover, potentially contributing to placental dysfunction and adverse pregnancy outcomes. COVID-19 / pathology COVID-19 / virology Cell Fusion Female Humans Placenta / pathology Placenta / virology Pregnancy Pregnancy Complications, Infectious / virology Pregnancy Trimester, First SARS-CoV-2 / pathogenicity SARS-CoV-2 / physiology Trophoblasts / pathology Trophoblasts / virology Virus Internalization Virus Replication Dewey 616 Dewey 616.07 Dewey 618 56 Département de médecine 221 58 Département de pédiatrie, gynécologie et obstétrique 223 137 Département de pathologie et immunologie 21F false 400 Virologie clinique 668 1255 Virus émergents 993 584 Laboratoire de biologie des tumeurs gynécologiques et du développement 927 Cell death and disease 16 1 c483c5b9-cc85-40c5-b9bb-691ca8e60afc Article (Published version) Public Article_scientifique_from_unpaywall.pdf 2857815 application/pdf CC BY-4.0 63e9b257a85ccae9cbd81ad30404a0f5ec75eafa4f62c82dd470f022fb0efea9 3eb60faa-64d1-4e2f-8d29-39795349003b Supplemental data Public 41419_2025_8016_MOESM1_ESM.docx 21664 application/vnd.openxmlformats-officedocument.wordprocessingml.document 32e20fe7bc40657621fbd491b2036e61417ced4ea8e4b95ce46e6400003695ac 5570eab1-72b9-48fd-9b1e-607d9b85b736 Supplemental data Public 41419_2025_8016_MOESM2_ESM.tif 1083440 image/tiff e8f4092b719b304f2d70eee486f2605943aa2110816698238ff7cef564f0a06d 7d40ba19-faf3-48a8-812f-906977835648 Supplemental data Public 41419_2025_8016_MOESM3_ESM.jpg 172874 image/jpeg 98342495df455e99827c7af6f3c3d03336a8a5bd85776d249093f462da404d00 openAccess Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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SARS-CoV-2 delta and omicron variants alter trophoblast cell fusion and syncytiotrophoblast dynamics : new insights into placental vulnerability	Cell death and disease			2025	41	53

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Wuillemin, Christine