Blood-brain barrier-restricted translocation of Toxoplasma gondii from cortical capillaries

  1. Gabriella C Olivera
  2. Emily C Ross
  3. Christiane Peuckert
  4. Antonio Barragan  Is a corresponding author
  1. Stockholm University, Sweden
  2. Department of Molecular Biosciences, The Wenner-Gren Institute, Sweden

Abstract

The cellular barriers of the central nervous system proficiently protect the brain parenchyma from infectious insults. Yet, the single-celled parasite Toxoplasma gondii commonly causes latent cerebral infection in humans and other vertebrates. Here, we addressed the role of the cerebral vasculature in the passage of T. gondii to the brain parenchyma. Shortly after inoculation in mice, parasites mainly localized to cortical capillaries, in preference over post-capillary venules, cortical arterioles or meningeal and choroidal vessels. Early invasion to the parenchyma (days 1-5) occurred in absence of a measurable increase in blood-brain barrier (BBB) permeability, perivascular leukocyte cuffs or hemorrhage. However, sparse focalized permeability elevations were detected adjacently to replicative parasite foci. Further, T. gondii triggered inflammatory responses in cortical microvessels and endothelium. Pro- and anti-inflammatory treatments of mice with LPS and hydrocortisone, respectively, impacted BBB permeability and parasite loads in the brain parenchyma. Finally, pharmacological inhibition or Cre/loxP conditional knockout of endothelial focal adhesion kinase (FAK), a BBB intercellular junction regulator, facilitated parasite translocation to the brain parenchyma. The data reveal that the initial passage of T. gondii to the central nervous system occurs principally across cortical capillaries. The integrity of the microvascular BBB restricts parasite transit, which conversely is exacerbated by the inflammatory response.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Gabriella C Olivera

    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  2. Emily C Ross

    Molecular Biosciences, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Christiane Peuckert

    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  4. Antonio Barragan

    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    For correspondence
    antonio.barragan@su.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7746-9964

Funding

Vetenskapsrådet (2018-02411)

  • Antonio Barragan

Olle Engkvist Foundation (193-609)

  • Antonio Barragan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experimentation was approved by the Regional Animal Research Ethical Board, Stockholm, Sweden, (protocol numbers N135/15, 9707-2018 and 14458-2019), following proceedings described in EU legislation (Council Directive 2010/63/EU).

Reviewing Editor

  1. Sebastian Lourido, Whitehead Institute for Biomedical Research, United States

Publication history

  1. Received: April 7, 2021
  2. Accepted: December 5, 2021
  3. Accepted Manuscript published: December 8, 2021 (version 1)
  4. Accepted Manuscript updated: December 9, 2021 (version 2)
  5. Version of Record published: December 23, 2021 (version 3)

Copyright

© 2021, Olivera et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Gabriella C Olivera
  2. Emily C Ross
  3. Christiane Peuckert
  4. Antonio Barragan
(2021)
Blood-brain barrier-restricted translocation of Toxoplasma gondii from cortical capillaries
eLife 10:e69182.
https://doi.org/10.7554/eLife.69182

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