Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients

  1. Matteo Bocci
  2. Clara Oudenaarden
  3. Xavier Sàenz-Sardà
  4. Joel Simrén
  5. Arvid Edén
  6. Jonas Sjölund
  7. Christina Möller
  8. Magnus Gisslén
  9. Henrik Zetterberg
  10. Elisabet Englund
  11. Kristian Pietras

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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.

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  1. Version published to 10.3390/ijms222111622
  2. ScreenIT

    SciScore for 10.1101/2021.05.24.445532: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The use of these samples has been approved by the Regional Ethical Committee in Gothenburg.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Following slide preparation, sections underwent staining cycles (Supplementary Table 4) —including blocking, primary antibody incubation, HRP tagging and labeling with OPAL-conjugated tyramide substrate— and a stripping procedure to remove unbound primary antibody/HRP.
    antibody/HRP
    suggested: None
    Software and Algorithms
    SentencesResources
    Heat-induced epitope retrieval was performed with a pressure cooker (2100 Antigen Retriever, BioVendor, Germany) in citrate or Tris-EDTA buffer (Agilent Dako, USA).
    BioVendor
    suggested: (BioVendor Laboratory Medicine, RRID:SCR_005143)
    Statistical Mann-Whitney U-test was performed using Prism (GraphPad Software, USA).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2021.05.24.445532v1 on bioRxiv