Trypanosoma brucei brucei crosses the blood–brain barrier while tight junction proteins are preserved in a rat chronic disease model

Abstract

African trypanosomiasis, sleeping sickness in humans, is caused by the systemic infection of the host by the extracellular parasite, the African trypanosome. The pathogenetic mechanisms of the severe symptoms of central nervous system involvement are still not well understood. The present study examined the routes of haematogenous spread of Trypanosoma brucei brucei (Tbb) to the brain, in particular on the question whether parasites can cross the blood-brain barrier, as well as their effect on tight junction proteins. Rats were infected with Tbb and at various times post-infection, the location of the parasite in the central nervous system was examined in relation to the brain vascular endothelium, visualized with an anti-glucose transporter-1 antibody. The tight junction-specific proteins occludin and zonula occludens 1, and the possible activation of the endothelial cell adhesion molecules ICAM-1 and VCAM-1 were also studied. At 12 and 22 days post-infection, the large majority of parasites were confined within blood vessels. At this stage, however, some parasites were also clearly observed in the brain parenchyma. This was accompanied by an upregulation of ICAM-1/VCAM-1. At later stages, 42, 45 and 55 days post-infection, parasites could still be detected within or in association with blood vessels. In addition, the parasite was now frequently found in the brain parenchyma and the extravasation of parasites was more prominent in the white matter than the cerebral cortex. A marked penetration of parasites was seen in the septal nuclei. In spite of this, occludin and zonula occludens 1 staining of the vessels was preserved. The results indicate that the Tbb parasite is able to cross the blood-brain barrier in vivo, without a generalized loss of tight junction proteins.

Identification of Stage Biomarkers for Human African Trypanosomiasis

“…Mice and rats show a similar outcome of T. b. brucei infection, and the penetration of parasites into the brain parenchyma occurs between 12 and 22 dpi. 26,27 It was observed that all transcripts for CXCL10, lipocalin 2, and SLPI were differentially upregulated in brains of infected rats at late stage similar to what was observed in mice ( Figure 3A-C ). Because of limitations in commercially available antibodies against rat proteins, only lipocalin 2 was analyzed in rat CSF.…”

Gene Knockdown of γ-Glutamylcysteine Synthetase by RNAi in the Parasitic Protozoa Trypanosoma brucei Demonstrates That It Is an Essential Enzyme

“…The addition of GSH to cell cultures rescued the RNA i cell death phenotype providing further proof that GSH is an essential metabolite in these parasites. Whereas this requirement for GSH can be supplied exogenously in vitro, T. brucei is an extracellular parasite in all stages of its life cycle (42,43). Thus the parasite does not have access to the intracellular thiol pools in the host likely constraining it to supply the growth requirement for GSH through de novo synthesis.…”

Cerebral vessel laminins and IFN-γ define Trypanosoma brucei brucei penetration of the blood-brain barrier

“…In experimental animals infected with the rodent pathogenic strain T. brucei brucei, parasites appear early during infection in the choroid plexus and other circumventricular organs (2) that lack a BBB. At later stages, the parasites penetrate the BBB and enter the brain parenchyma, as revealed by double immunohistochemical labeling of parasites and brain endothelial cells in a rat model of the chronic disease (3). A larger number of parasites appear in the white matter and in the septal nuclei rather than in the cerebral neocortex.…”