Brain exposure to SARS-CoV-2 virions perturbs synaptic homeostasis

  • Nat Microbiol. 2024 May;9(5):1189-1206. doi: 10.1038/s41564-024-01657-2.
Emma Partiot  1  2 ,  Aurélie Hirschler  3  4 ,  Sophie Colomb  5  6 ,  Willy Lutz  1  2  7 ,  Tine Claeys  8  9 ,  François Delalande  3  4 ,  Maika S Deffieu  1  2 ,  Yonis Bare  1  2 ,  Judith R E Roels  10 ,  Barbara Gorda  1  2 ,  Joanna Bons  3  4 ,  Domitille Callon  11  12 ,  Laurent Andreoletti  11  12 ,  Marc Labrousse  12  13 ,  Frank M J Jacobs  10 ,  Valérie Rigau  2  14 ,  Benoit Charlot  2  15 ,  Lennart Martens  8  9 ,  Christine Carapito  3  4 ,  Gowrishankar Ganesh  2  7 ,  Raphael Gaudin  16  17
Affiliations
  • 1. CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France.
  • 2. Univ Montpellier, Montpellier, France.
  • 3. Laboratoire de Spectrométrie de Masse Bio-Organique, IPHC, UMR 7178, CNRS-Université de Strasbourg, Strasbourg, France.
  • 4. Infrastructure Nationale de Protéomique ProFI─FR2048, Strasbourg, France.
  • 5. EDPFM (Equipe de Droit Pénal et de Sciences Forensiques de Montpellier), Univ Montpellier, Montpellier, France.
  • 6. Emergency Pole, Forensic Medicine Department, Montpellier University Hospital, Montpellier, France.
  • 7. UM-CNRS Laboratoire d'Informatique de Robotique et de Microelectronique de Montpellier (LIRMM), Montpellier, France.
  • 8. VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
  • 9. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • 10. Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
  • 11. University of Reims Champagne-Ardenne, Medicine Faculty, Laboratory of Virology, CardioVir UMR-S 1320, Reims, France.
  • 12. Forensic, Virology and ENT Departments, University Hospital Centre (CHU), Reims, France.
  • 13. Anatomy laboratory, UFR Médecine, Université de Reims Champagne-Ardenne, Reims, France.
  • 14. Pathological Department and Biological Resources Center BRC, Montpellier University Hospital, 'Cerebral plasticity, Stem cells and Glial tumors' team. IGF- Institut de génomique fonctionnelle INSERM U 1191 - CNRS UMR 5203, Univ Montpellier, Montpellier, France.
  • 15. Institut d'Electronique et des Systèmes (IES), CNRS, Montpellier, France.
  • 16. CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France. [email protected].
  • 17. Univ Montpellier, Montpellier, France. [email protected].
PMID: 38548923 DOI: 10.1038/s41564-024-01657-2
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection is associated with short- and long-term neurological complications. The variety of symptoms makes it difficult to unravel molecular mechanisms underlying neurological sequalae after coronavirus disease 2019 (COVID-19). Here we show that SARS-CoV-2 triggers the up-regulation of synaptic components and perturbs local electrical field potential. Using cerebral organoids, organotypic culture of human brain explants from individuals without COVID-19 and post-mortem brain samples from individuals with COVID-19, we find that neural cells are permissive to SARS-CoV-2 to a low extent. SARS-CoV-2 induces aberrant presynaptic morphology and increases expression of the synaptic components Bassoon, latrophilin-3 (LPHN3) and fibronectin leucine-rich transmembrane protein-3 (FLRT3). Furthermore, we find that LPHN3-agonist treatment with Stachel partially restored Organoid electrical activity and reverted SARS-CoV-2-induced aberrant presynaptic morphology. Finally, we observe accumulation of relatively static virions at LPHN3-FLRT3 synapses, suggesting that local hindrance can contribute to synaptic perturbations. Together, our study provides molecular insights into SARS-CoV-2-brain interactions, which may contribute to COVID-19-related neurological disorders.

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