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SARS-CoV-2 spike protein induces brain pericyte immunoreactivity in absence of productive viral infection

View ORCID ProfileRayan Khaddaj-Mallat, Natija Aldib, Anne-Sophie Paquette, Aymeric Ferreira, Sarah Lecordier, Maxime Bernard, View ORCID ProfileArmen Saghatelyan, View ORCID ProfileAyman ElAli
doi: https://doi.org/10.1101/2021.04.30.442194
Rayan Khaddaj-Mallat
1Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada
3Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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  • ORCID record for Rayan Khaddaj-Mallat
Natija Aldib
1Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada
2Research Center CERVO, Quebec City, QC, Canada
3Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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Anne-Sophie Paquette
1Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada
3Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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Aymeric Ferreira
2Research Center CERVO, Quebec City, QC, Canada
3Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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Sarah Lecordier
1Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada
3Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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Maxime Bernard
1Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada
3Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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Armen Saghatelyan
2Research Center CERVO, Quebec City, QC, Canada
3Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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  • ORCID record for Armen Saghatelyan
Ayman ElAli
1Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada
3Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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  • For correspondence: ayman.el-ali@crchudequebec.ulaval.ca
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Abstract

COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via still elusive mechanisms. SARS-CoV-2 infects host cells by binding to angiotensin-converting enzyme 2 (ACE2), a transmembrane receptor that recognizes the viral spike (S) protein. Brain pericytes were recently shown to express ACE2 at the neurovascular interface, outlining their possible implication in microvasculature injury in COVID-19. Yet, pericyte responses to SARS-CoV-2 is still to be fully elucidated. Using cell-based assays, we report that ACE2 expression in human brain vascular pericytes is highly dynamic and is increased upon S protein stimulation. Pericytes exposed to S protein underwent profound phenotypic changes translated by increased expression of contractile and myofibrogenic proteins, namely α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). These changes were associated to an altered intracellular calcium (Ca2+) dynamic. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signalling pathway, which was potentiated by hypoxia, a condition associated to vascular comorbidities, which exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely interleukin-8 (IL-8), IL-18, macrophage migration inhibitory factor (MIF), and stromal cell-derived factor-1 (SDF-1). Finally, we found that S protein could reach the mouse brain via the intranasal route and that reactive ACE2-expressing pericytes are recruited to the damaged tissue undergoing fibrotic scarring in a mouse model of cerebral multifocal micro-occlusions, a main reported vascular-mediated neurological condition associated to COVID-19. Our data demonstrate that the released S protein is sufficient to mediate pericyte immunoreactivity, which may contribute to microvasculature injury in absence of a productive viral infection. Our study provides a better understanding for the possible mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 03, 2021.
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SARS-CoV-2 spike protein induces brain pericyte immunoreactivity in absence of productive viral infection
Rayan Khaddaj-Mallat, Natija Aldib, Anne-Sophie Paquette, Aymeric Ferreira, Sarah Lecordier, Maxime Bernard, Armen Saghatelyan, Ayman ElAli
bioRxiv 2021.04.30.442194; doi: https://doi.org/10.1101/2021.04.30.442194
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SARS-CoV-2 spike protein induces brain pericyte immunoreactivity in absence of productive viral infection
Rayan Khaddaj-Mallat, Natija Aldib, Anne-Sophie Paquette, Aymeric Ferreira, Sarah Lecordier, Maxime Bernard, Armen Saghatelyan, Ayman ElAli
bioRxiv 2021.04.30.442194; doi: https://doi.org/10.1101/2021.04.30.442194

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