Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (<i>...

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Autores principales:	Matteo Bocci, Clara Oudenaarden, Xavier Sàenz-Sardà, Joel Simrén, Arvid Edén, Jonas Sjölund, Christina Möller, Magnus Gisslén, Henrik Zetterberg, Elisabet Englund, Kristian Pietras
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	COVID-19 pericytes ACE2 SARS-CoV-2 blood–brain barrier multiplexed IHC Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/aa3a224fe4a946ba8e284aa603265ede
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spelling	oai:doaj.org-article:aa3a224fe4a946ba8e284aa603265ede2021-11-11T17:06:02ZInfection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients10.3390/ijms2221116221422-00671661-6596https://doaj.org/article/aa3a224fe4a946ba8e284aa603265ede2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11622https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (<i>n</i> = 6 COVID-19, median age = 69.5 years; <i>n</i> = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood–brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (<i>n</i> = 8 COVID-19, median age = 67 years; <i>n</i> = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood–brain barrier.Matteo BocciClara OudenaardenXavier Sàenz-SardàJoel SimrénArvid EdénJonas SjölundChristina MöllerMagnus GisslénHenrik ZetterbergElisabet EnglundKristian PietrasMDPI AGarticleCOVID-19pericytesACE2SARS-CoV-2blood–brain barriermultiplexed IHCBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11622, p 11622 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 pericytes ACE2 SARS-CoV-2 blood–brain barrier multiplexed IHC Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	COVID-19 pericytes ACE2 SARS-CoV-2 blood–brain barrier multiplexed IHC Biology (General) QH301-705.5 Chemistry QD1-999 Matteo Bocci Clara Oudenaarden Xavier Sàenz-Sardà Joel Simrén Arvid Edén Jonas Sjölund Christina Möller Magnus Gisslén Henrik Zetterberg Elisabet Englund Kristian Pietras Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients
description	A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (<i>n</i> = 6 COVID-19, median age = 69.5 years; <i>n</i> = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood–brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (<i>n</i> = 8 COVID-19, median age = 67 years; <i>n</i> = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood–brain barrier.
format	article
author	Matteo Bocci Clara Oudenaarden Xavier Sàenz-Sardà Joel Simrén Arvid Edén Jonas Sjölund Christina Möller Magnus Gisslén Henrik Zetterberg Elisabet Englund Kristian Pietras
author_facet	Matteo Bocci Clara Oudenaarden Xavier Sàenz-Sardà Joel Simrén Arvid Edén Jonas Sjölund Christina Möller Magnus Gisslén Henrik Zetterberg Elisabet Englund Kristian Pietras
author_sort	Matteo Bocci
title	Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients
title_short	Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients
title_full	Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients
title_fullStr	Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients
title_full_unstemmed	Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients
title_sort	infection of brain pericytes underlying neuropathology of covid-19 patients
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/aa3a224fe4a946ba8e284aa603265ede
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Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients

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