Blood-brain barrier-restricted translocation of Toxoplasma gondii from cortical capillaries
- Stockholm University, Sweden
- 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
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).
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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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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