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

eLife

Emily C Ross¹  Christiane Peuckert¹  Antonio Barragan¹  Gabriela C Olivera¹ 

[1] Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden;

关键词: apicomplexa;    blood-brain barrier;    CNS infection;    Toxoplasma gondii;    biological barriers;    inflammation;    Mouse;   

DOI  :  10.7554/eLife.69182

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY