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?
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...
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University of Münster / Open Journals System
2023-02-01
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| Series: | Free Neuropathology |
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| Online Access: | https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/4584 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Susana Boluda |
| collection | DOAJ |
| description |
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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| first_indexed | 2024-04-10T15:52:22Z |
| format | Article |
| id | doaj.art-05edf363d5d14e9389cc5d0000462bdb |
| institution | Directory Open Access Journal |
| issn | 2699-4445 |
| language | English |
| last_indexed | 2024-04-10T15:52:22Z |
| publishDate | 2023-02-01 |
| publisher | University of Münster / Open Journals System |
| record_format | Article |
| series | Free Neuropathology |
| spelling | doaj.art-05edf363d5d14e9389cc5d0000462bdb2023-02-11T02:04:35ZengUniversity of Münster / Open Journals SystemFree Neuropathology2699-44452023-02-01410.17879/freeneuropathology-2023-4584Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?Susana Boluda0Karima Mokhtari1Bruno Mégarbane2Djillali Annane3Bertrand Mathon4Albert Cao5Clovis Adam6Alexandre Androuin7Franck Bielle8Guy Brochier9Frédéric Charlotte10Lydia Chougar11Khalid Hamid El Hachimi12Marc Eloit13Stéphane Haïk14Dominique Hervé15Amal Kasri16Valentin Leducq17Stéphane Lehéricy18Etienne Levavasseur19Christian Lobsiger20Geoffroy Lorin de La Grandmaison21Isabelle Malet22Isabelle Malissin23Stéphane Marot24Serge Marty25Philippe Pérot26Isabelle Plu27Annick Prigent28Lev Stimmer29Marie-Claude Potier30Anne-Geneviève Marcelin31Benoît Delatour32Charles Duyckaerts33Danielle Seilhean34Department 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, FranceDepartment 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, FranceDepartment of Medical and Toxicological Critical Care, Lariboisière Hospital, AP-HP, Paris University, INSERM UMRS-1144, Paris, FranceDepartment of Critical Care, Raymond Poincaré Hospital, Boulevard Raymond Poincaré, APHP, Paris-Saclay University, INSERM U1173, Garches, FranceDepartment of Neurosurgery, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, FranceDepartment of Neurology, Neuro-ICU, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, FranceDepartment of Pathology, Bicêtre Hospital, AP-HP, Paris Saclay University, Le Kremlin-Bicêtre, FranceInstitut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, FranceDepartment 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, FranceDepartment of Neuropathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France; Institut de Myologie, Pitié-Salpêtrière Hospital, Paris, FranceDepartment of Pathology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, FranceDepartment of Neuroimaging, Pitié-Salpètrière Hospital, AP-HP Sorbonne University, Paris, FranceInstitut 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, FranceInstitut Pasteur, Pathogen Discovery Laboratory, Paris, FranceDepartment 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, FranceDepartment of Neurology, Lariboisière Hospital, AP-HP Nord- Paris University, Paris, FranceInstitut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, FranceDepartment of Virology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Paris, FranceDepartment of Neuroimaging, Pitié-Salpètrière Hospital, AP-HP Sorbonne University, Paris, FranceDepartment 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, FranceInstitut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, FranceDepartment of Forensic Medicine and Pathology, Raymond Poincaré Hospital, AP-HP, Paris Saclay University, Garches, FranceDepartment of Virology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Paris, FranceDepartment of Medical and Toxicological Critical Care, Lariboisière Hospital, AP-HP, Paris University, INSERM UMRS-1144, Paris, FranceDepartment of Virology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Paris, FranceInstitut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, FranceInstitut Pasteur, Pathogen Discovery Laboratory, Paris, FranceDepartment 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, FranceInstitut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, FranceInstitut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, FranceInstitut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, FranceDepartment of Virology, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, INSERM 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Paris, FranceInstitut du Cerveau - Paris Brain Institute - ICM, Inserm U1127, CNRS UMR7225, APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, FranceDepartment 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, FranceDepartment 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 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. https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/4584COVID-19Neuro-COVIDMicroangiopathyFurinBlood-brain barrier (BBB) |
| spellingShingle | 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 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 COVID-19 Neuro-COVID Microangiopathy Furin Blood-brain barrier (BBB) |
| title | 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? |
| title_full | 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? |
| title_fullStr | 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? |
| title_full_unstemmed | 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? |
| title_short | 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? |
| title_sort | 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 |
| topic | COVID-19 Neuro-COVID Microangiopathy Furin Blood-brain barrier (BBB) |
| url | https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/4584 |
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