Delineating neuroinflammation, parasite CNS invasion, and blood-brain barrier dysfunction in an experimental murine model of human African trypanosomiasis

Rodgers, J. , Bradley, B. and Kennedy, P. G.E. (2017) Delineating neuroinflammation, parasite CNS invasion, and blood-brain barrier dysfunction in an experimental murine model of human African trypanosomiasis. Methods, 127, pp. 79-87. (doi:10.1016/j.ymeth.2017.06.015) (PMID:28636879) (PMCID:PMC5595161)

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Abstract

Although Trypanosoma brucei spp. was first detected by Aldo Castellani in CSF samples taken from sleeping sickness patients over a century ago there is still a great deal of debate surrounding the timing, route and effects of transmigration of the parasite from the blood to the CNS. In this investigation, we have applied contrast-enhance magnetic resonance imaging (MRI) to study the effects of trypanosome infection on the blood-brain barrier (BBB) in the well-established GVR35 mouse model of sleeping sickness. In addition, we have measured the trypanosome load present in the brain using quantitative Taqman PCR and assessed the severity of the neuroinflammatory reaction at specific time points over the course of the infection. Contrast enhanced – MRI detected a significant degree of BBB impairment in mice at 14 days following trypanosome infection, which increased in a step-wise fashion as the disease progressed. Parasite DNA was present in the brain tissue on day 7 after infection. This increased significantly in quantity by day 14 post-infection and continued to rise as the infection advanced. A progressive increase in neuroinflammation was detected following trypanosome infection, reaching a significant level of severity on day 14 post-infection and rising further at later time-points. In this model stage-2 disease presents at 21 days post-infection. The combination of the three methodologies indicates that changes in the CNS become apparent prior to the onset of established stage-2 disease. This could in part account for the difficulties associated with defining specific criteria to distinguish stage-1 and stage-2 infections and highlights the need for improved staging diagnostics.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kennedy, Professor Peter and Bradley, Mrs Barbara and Rodgers, Dr Jean
Authors: Rodgers, J., Bradley, B., and Kennedy, P. G.E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Methods
Publisher:Elsevier
ISSN:1046-2023
ISSN (Online):1095-9130
Published Online:19 June 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Methods 127: 79-87
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
554901Defining the role of kynurenine pathway metabolites in the inflammatory response to trypanosome invasion of the CNSPeter KennedyWellcome Trust (WELLCOTR)094691/Z/10/ZIII - PARASITOLOGY