SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein

Coronavirus disease 19 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via elusive mechanisms. SARS-CoV-2 infects host cells via the binding of viral Spike (S) protein to...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Rayan Khaddaj-Mallat, Natija Aldib, Maxime Bernard, Anne-Sophie Paquette, Aymeric Ferreira, Sarah Lecordier, Armen Saghatelyan, Louis Flamand, Ayman ElAli
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	COVID-19 SARS-CoV-2 S protein Pericytes Neurovascular interface Cerebrovascular disorders Inflammation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/672bcb1f4966497e9c8ad00e6c3f33c4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:672bcb1f4966497e9c8ad00e6c3f33c4
record_format	dspace
spelling	oai:doaj.org-article:672bcb1f4966497e9c8ad00e6c3f33c42021-12-04T04:33:14ZSARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein1095-953X10.1016/j.nbd.2021.105561https://doaj.org/article/672bcb1f4966497e9c8ad00e6c3f33c42021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121003107https://doaj.org/toc/1095-953XCoronavirus disease 19 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via elusive mechanisms. SARS-CoV-2 infects host cells via the binding of viral Spike (S) protein to transmembrane receptor, angiotensin-converting enzyme 2 (ACE2). Although brain pericytes were recently shown to abundantly express ACE2 at the neurovascular interface, their response to SARS-CoV-2 S protein is still to be elucidated. Using cell-based assays, we found that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure promoted the acquisition of calcium (Ca2+) signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca2+ fluctuations. 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) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that 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 macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein accumulated in the intranasal cavity reached the brain of mice in which the nasal mucosa is deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.Rayan Khaddaj-MallatNatija AldibMaxime BernardAnne-Sophie PaquetteAymeric FerreiraSarah LecordierArmen SaghatelyanLouis FlamandAyman ElAliElsevierarticleCOVID-19SARS-CoV-2 S proteinPericytesNeurovascular interfaceCerebrovascular disordersInflammationNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 161, Iss , Pp 105561- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 SARS-CoV-2 S protein Pericytes Neurovascular interface Cerebrovascular disorders Inflammation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	COVID-19 SARS-CoV-2 S protein Pericytes Neurovascular interface Cerebrovascular disorders Inflammation Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Rayan Khaddaj-Mallat Natija Aldib Maxime Bernard Anne-Sophie Paquette Aymeric Ferreira Sarah Lecordier Armen Saghatelyan Louis Flamand Ayman ElAli SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein
description	Coronavirus disease 19 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via elusive mechanisms. SARS-CoV-2 infects host cells via the binding of viral Spike (S) protein to transmembrane receptor, angiotensin-converting enzyme 2 (ACE2). Although brain pericytes were recently shown to abundantly express ACE2 at the neurovascular interface, their response to SARS-CoV-2 S protein is still to be elucidated. Using cell-based assays, we found that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure promoted the acquisition of calcium (Ca2+) signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca2+ fluctuations. 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) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that 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 macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein accumulated in the intranasal cavity reached the brain of mice in which the nasal mucosa is deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.
format	article
author	Rayan Khaddaj-Mallat Natija Aldib Maxime Bernard Anne-Sophie Paquette Aymeric Ferreira Sarah Lecordier Armen Saghatelyan Louis Flamand Ayman ElAli
author_facet	Rayan Khaddaj-Mallat Natija Aldib Maxime Bernard Anne-Sophie Paquette Aymeric Ferreira Sarah Lecordier Armen Saghatelyan Louis Flamand Ayman ElAli
author_sort	Rayan Khaddaj-Mallat
title	SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein
title_short	SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein
title_full	SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein
title_fullStr	SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein
title_full_unstemmed	SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein
title_sort	sars-cov-2 deregulates the vascular and immune functions of brain pericytes via spike protein
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/672bcb1f4966497e9c8ad00e6c3f33c4
work_keys_str_mv	AT rayankhaddajmallat sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein AT natijaaldib sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein AT maximebernard sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein AT annesophiepaquette sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein AT aymericferreira sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein AT sarahlecordier sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein AT armensaghatelyan sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein AT louisflamand sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein AT aymanelali sarscov2deregulatesthevascularandimmunefunctionsofbrainpericytesviaspikeprotein
_version_	1718372971068784640

SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein

Ejemplares similares