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: | Montague, Dr Paul and Kennedy, Professor Peter and Bradley, Mrs Barbara and Rodgers, Dr Jean |
| 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 > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| 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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