Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?

Authors

  • Susana Boluda Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Karima Mokhtari Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Bruno Mégarbane Department of Medical and Toxicological Critical Care, Lariboisière Hospital, AP-HP, Paris University, INSERM UMRS-1144, Paris, France
  • Djillali Annane Department of Critical Care, Raymond Poincaré Hospital, Boulevard Raymond Poincaré, APHP, Paris-Saclay University, INSERM U1173, Garches, France
  • Bertrand Mathon Department of Neurosurgery, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France
  • Albert Cao Department of Neurology, Neuro-ICU, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France
  • Clovis Adam Department of Pathology, Bicêtre Hospital, AP-HP, Paris Saclay University, Le Kremlin-Bicêtre, France
  • Alexandre Androuin Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Franck Bielle Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Guy Brochier Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut de Myologie, Pitié-Salpêtrière Hospital, Paris, France
  • Frédéric Charlotte Department of Pathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France
  • Lydia Chougar Department of Neuroimaging, Pitié-Salpètrière Hospital, AP-HP Sorbonne University, Paris, France
  • Khalid Hamid El Hachimi Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France; Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences et Lettres (PSL) University, Paris, France
  • Marc Eloit Institut Pasteur, Pathogen Discovery Laboratory, Paris, France
  • Stéphane Haïk Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Dominique Hervé Department of Neurology, Lariboisière Hospital, AP-HP Nord- Paris University, Paris, France
  • Amal Kasri Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Valentin Leducq Department of Virology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Paris, France
  • Stéphane Lehéricy Department of Neuroimaging, Pitié-Salpètrière Hospital, AP-HP Sorbonne University, Paris, France
  • Etienne Levavasseur Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Christian Lobsiger Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Geoffroy Lorin de La Grandmaison Department of Forensic Medicine and Pathology, Raymond Poincaré Hospital, AP-HP, Paris Saclay University, Garches, France
  • Isabelle Malet Department of Virology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Paris, France
  • Isabelle Malissin Department of Medical and Toxicological Critical Care, Lariboisière Hospital, AP-HP, Paris University, INSERM UMRS-1144, Paris, France
  • Stéphane Marot Department of Virology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Paris, France
  • Serge Marty Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Philippe Pérot Institut Pasteur, Pathogen Discovery Laboratory, Paris, France
  • Isabelle Plu Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Annick Prigent Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Lev Stimmer Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Marie-Claude Potier Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Anne-Geneviève Marcelin Department of Virology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Paris, France
  • Benoît Delatour Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Charles Duyckaerts Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
  • Danielle Seilhean Department of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France

DOI:

https://doi.org/10.17879/freeneuropathology-2023-4584

Keywords:

COVID-19, Neuro-COVID, Microangiopathy, Furin, Blood-brain barrier (BBB)

Abstract

In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells in vitro and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy.

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Published

2023-02-10

How to Cite

Boluda, S., Mokhtari, K., Mégarbane, B., Annane, D., Mathon, B., Cao, A., Adam, C., Androuin, A., Bielle, F., Brochier, G., Charlotte, F., Chougar, L., El Hachimi, K. H., Eloit, M., Haïk, S., Hervé, D., Kasri, A., Leducq, V., Lehéricy, S., Levavasseur, E., Lobsiger, C., Lorin de La Grandmaison, G., Malet, I., Malissin, I., Marot, S., Marty, S., Pérot, P., Plu, I., Prigent, A., Stimmer, L., Potier, M.-C., Marcelin, A.-G., Delatour, B., Duyckaerts, C., & Seilhean, D. (2023). Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?. Free Neuropathology, 4, 1. https://doi.org/10.17879/freeneuropathology-2023-4584

Issue

Vol. 4 (2023)

Section

Original Papers

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Copyright (c) 2023 Susana Boluda, Karima Mokhtari, Bruno Mégarbane, Djillali Annane, Bertrand Mathon, Albert Cao, Clovis Adam, Alexandre Androuin, Franck Bielle, Guy Brochier, Frédéric Charlotte, Lydia Chougar, Khalid Hamid El Hachimi, Marc Eloit, Stéphane Haïk, Dominique Hervé, Amal Kasri, Valentin Leducq, Stéphane Lehéricy, Etienne Levavasseur, Christian Lobsiger, Geoffroy Lorin de La Grandmaison, Isabelle Malet, Isabelle Malissin, Stéphane Marot, Serge Marty, Philippe Pérot, Isabelle Plu, Annick Prigent, Lev Stimmer, Marie-Claude Potier, Anne-Geneviève Marcelin, Benoît Delatour, Charles Duyckaerts, Danielle Seilhean

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