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Infection of brain pericytes underlying neuropathology of covid‐19 patients

Bocci, Matteo LU orcid ; Oudenaarden, Clara LU ; Sàenz‐sardà, Xavier ; Simrén, Joel ; Edén, Arvid ; Sjölund, Jonas LU ; Möller, Christina LU ; Gisslén, Magnus ; Zetterberg, Henrik LU and Englund, Elisabet LU orcid , et al. (2021) In International Journal of Molecular Sciences 22(21).
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 sympto-matology 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 neuro-vascular 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... (More)

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 sympto-matology 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 neuro-vascular 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 macro-phage 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ACE2, Blood–brain barrier, Brain, COVID‐19, Infection, Multiplexed IHC, Pericytes, SARS‐CoV‐2, Vasculature
in
International Journal of Molecular Sciences
volume
22
issue
21
article number
11622
publisher
MDPI AG
external identifiers
  • scopus:85117966340
  • pmid:34769052
ISSN
1661-6596
DOI
10.3390/ijms222111622
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
id
fec75098-c902-49b4-821a-17dcfb51263d
date added to LUP
2021-11-07 07:09:30
date last changed
2024-04-20 14:53:26
@article{fec75098-c902-49b4-821a-17dcfb51263d,
  abstract     = {{<p>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 sympto-matology 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 neuro-vascular 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 macro-phage 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.</p>}},
  author       = {{Bocci, Matteo and Oudenaarden, Clara and Sàenz‐sardà, Xavier and Simrén, Joel and Edén, Arvid and Sjölund, Jonas and Möller, Christina and Gisslén, Magnus and Zetterberg, Henrik and Englund, Elisabet and Pietras, Kristian}},
  issn         = {{1661-6596}},
  keywords     = {{ACE2; Blood–brain barrier; Brain; COVID‐19; Infection; Multiplexed IHC; Pericytes; SARS‐CoV‐2; Vasculature}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{21}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Infection of brain pericytes underlying neuropathology of covid‐19 patients}},
  url          = {{http://dx.doi.org/10.3390/ijms222111622}},
  doi          = {{10.3390/ijms222111622}},
  volume       = {{22}},
  year         = {{2021}},
}