Infection of brain pericytes underlying neuropathology of COVID-19 patients

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

View ORCID ProfileKristian Pietras

doi: https://doi.org/10.1101/2021.05.24.445532

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.05.24.445532v1.full.pdf

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; and 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 peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and 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 peri-vascular inflammation and a locally compromised blood-brain barrier.

Competing Interest Statement

KP is a scientific advisor for Baxter and Pfizer, recipient of research grants from Acceleron Pharma, and a minority stock owner of Paracrine Therapeutics. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work).

https://www.biorxiv.org/content/10.1101/2021.05.24.445532v1