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?

Susana Boluda (1) , Karima Mokhtari (1) , Bruno Mégarbane (2, 3) , Djillali Annane (4, 5, 6) , Bertrand Mathon (7) , Albert Cao (7) , Clovis Adam (8, 5) , Alexandre Androuin (1) , Franck Bielle (1) , Guy Brochier (7, 9) , Frédéric Charlotte (7) , Lydia Chougar (7) , Hamid Khalid (1, 10) , Marc Eloit (11) , Stéphane Haïk (1) , Dominique Hervé (3, 12) , Amal Kasri (1) , Valentin Leducq (7, 13) , Stéphane Lehéricy (7) , Etienne Levavasseur (1) , Christian Lobsiger (1) , Geoffroy Lorin La Grandmaison (4, 5) , Isabelle Malet (7, 13) , Isabelle Malissin (3, 2) , Stéphane Marot (7, 13) , Serge Marty (1) , Philippe Pérot (11) , Isabelle Plu (1) , Annick Prigent (1) , Lev Stimmer (1) , Marie-Claude Potier (1) , Anne-Geneviève Marcelin (7, 13) , Benoît Delatour (1) , Charles Duyckaerts (1) , Danielle Seilhean (1)

1 ICM - Institut du Cerveau = Paris Brain Institute
2 OPTeN (UMR_S_1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
3 Hôpital Lariboisière-Fernand-Widal [APHP]
4 Hôpital Raymond Poincaré [Garches]
5 Université Paris-Saclay
6 2I - Infection et inflammation
7 CHU Pitié-Salpêtrière [AP-HP]
8 AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
9 Institut de Myologie
10 EPHE - École pratique des hautes études
11 Découverte de pathogènes – Pathogen discovery
12 Université Sorbonne Paris Nord
13 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique

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 bloodbrain-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.

Keywords: COVID-19; Neuro-Covid; Microangiopathy; Furin; Blood-brain barrier (BBB)

Domains: Life Sciences [q-bio]; Human health and pathology; Tissues and Organs [q-bio.TO]; Life Sciences [q-bio]; Microbiology and Parasitology; Virology

Susana Boluda, Karima Mokhtari, Bruno Mégarbane, Djillali Annane, Bertrand Mathon, et al.. 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, 2023, 4 (1), ⟨10.17879/freeneuropathology-2023-4584⟩. ⟨pasteur-04016681⟩