Microarray profiling predicts early neurological and immune phenotypic traits in advance of CNS disease during disease progression in Trypanosoma.b.brucei infected CD1 mouse brains

Montague, P., Bradley, B., Rodgers, J. and Kennedy, P. G.E. (2021) Microarray profiling predicts early neurological and immune phenotypic traits in advance of CNS disease during disease progression in Trypanosoma.b.brucei infected CD1 mouse brains. PLoS Neglected Tropical Diseases, 15(11), e0009892. (doi: 10.1371/journal.pntd.0009892) (PMID:34762691) (PMCID:PMC8584711)

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Abstract

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. We hypothesised that recent findings of neurological features and parasite brain infiltration occurring at much earlier stages in HAT than previously thought could be explained by early activation of host genetic programmes controlling CNS disease. Accordingly, a transcriptomal analysis was performed on brain tissue at 0, 7, 14, 21 and 28dpi from the HAT CD1/GVR35 mouse model. Up to 21dpi, most parasites are restricted to the blood and lymphatic system. Thereafter the trypanosomes enter the brain initiating the encephalitic stage. Analysis of ten different time point Comparison pairings, revealed a dynamic transcriptome comprising four message populations. All 7dpi Comparisons had by far more differentially expressed genes compared to all others. Prior to invasion of the parenchyma, by 7dpi, ~2,000 genes were up-regulated, denoted [7dpi↑] in contrast to a down regulated population [7dpi↓] also numbering ~2,000. However, by 14dpi both patterns had returned to around the pre-infected levels. The third, [28dpi↑] featured over three hundred transcripts which had increased modestly up to14dpi, thereafter were significantly up-regulated and peaked at 28dpi. The fourth, a minor population, [7dpi↑-28dpi↑], had similar elevated levels at 7dpi and 28dpi. KEGG and GO enrichment analysis predicted a diverse phenotype by 7dpi with changes to innate and adaptive immunity, a Type I interferon response, neurotransmission, synaptic plasticity, pleiotropic signalling, circadian activity and vascular permeability without disruption of the blood brain barrier. This key observation is consistent with recent rodent model neuroinvasion studies and clinical reports of Stage 1 HAT patients exhibiting CNS symptoms. Together, these findings challenge the strict Stage1/Stage2 phenotypic demarcation in HAT and show that that significant neurological, and immune changes can be detected prior to the onset of CNS disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bradley, Mrs Barbara and Montague, Dr Paul and Rodgers, Dr Jean and Kennedy, Professor Peter
Creator Roles:
Montague, P.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Writing – original draft
Bradley, B.Data curation, Investigation, Methodology, Visualization
Rodgers, J.Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review and editing
Kennedy, P. G.E.Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing – review and editing
Authors: Montague, P., Bradley, B., Rodgers, J., 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
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:PLoS Neglected Tropical Diseases
Publisher:Public Library of Science
ISSN:1935-2727
ISSN (Online):1935-2735
Published Online:11 November 2021
Copyright Holders:Copyright © 2021 Montague et al.
First Published:First published in PLoS Neglected Tropical Diseases 15(11): e0009892
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190378Defining the role of kynurenine pathway metabolites in the inflammatory response to trypanosome invasion of the CNSPeter KennedyWellcome Trust (WELLCOTR)094691/Z/10/ZIII - Parasitology