Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients.

Matteo Bocci,Henrik Zetterberg,Clara Oudenaarden,Christina Möller,Arvid Edén,Elisabet Englund,Joel Simrén,Kristian Pietras,Jonas Sjölund,Xavier Sàenz-Sardà,Magnus Gisslén

doi:10.3390/ijms222111622

Abstract

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 (n = 6 COVID-19, median age = 69.5 years; n = 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 (n = 8 COVID-19, median age = 67 years; n = 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.

Highlights

The clinical manifestations of coronavirus disease 2019 (COVID-19) infection primarily include respiratory symptoms, ranging from a mild cough to severe bilateral pneumonia [1,2]
The few published studies detailing the expression of angiotensin-converting enzyme 2 (ACE2) and/or SARS-CoV-2 protein in the central nervous system (CNS) lack reliable and appropriate controls, precluding firm conclusions
By means of highly sensitive multiplexed immunohistochemistry (mIHC) and the use of both positive and negative control tissues, we were able to confirm that ACE2 exhibited an exclusive perivascular expression pattern in the CNS

Summary

Introduction

The clinical manifestations of coronavirus disease 2019 (COVID-19) infection primarily include respiratory symptoms, ranging from a mild cough to severe bilateral pneumonia [1,2]. The involvement of the central nervous system (CNS) encompasses a broad spectrum of neurological manifestations (including headache, fatigue, anosmia, ageusia, confusion, and loss of consciousness), often representing an ulterior clinical morbidity that significantly contributes to COVID-19-related deaths [6,7,8]. Using highly sensitive multiplexed immunohistochemistry (mIHC) of brain tissue from a series of confirmed COVID-19 patients and corresponding controls, we determined that ACE2 is exclusively expressed by brain pericytes in the subset of patients that exhibited neurological symptoms. Spatial immunophenotyping revealed a localized perivascular inflammation in brain tissue from COVID-19 patients, paralleled by an impairment of the functionality of the vascular wall as indicated by loss of integrity of the blood–brain barrier (BBB). Our findings highlight a previously unappreciated role for brain pericytes in acting as pioneers for SARS-CoV-2 entry into the CNS

Methods

Results

Conclusion