Quintana, J. F. et al. (2023) The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronic Trypanosoma brucei infection. PLoS Biology, 21(11), e3002389. (doi: 10.1371/journal.pbio.3002389) (PMID:37983289) (PMCID:PMC10723712)
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Abstract
The meningeal space is a critical brain structure providing immunosurveillance for the central nervous system (CNS), but the impact of infections on the meningeal immune landscape is far from being fully understood. The extracellular protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis (HAT) or sleeping sickness, accumulates in the meningeal spaces, ultimately inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, by combining single-cell transcriptomics and mass cytometry by time-of-flight (CyTOF) with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges. These infection-induced ELAs were defined by the presence of ER-TR7+ fibroblastic reticular cells, CD21/35+ follicular dendritic cells (FDCs), CXCR5+ PD1+ T follicular helper-like phenotype, GL7+ CD95+ GC-like B cells, and plasmablasts/plasma cells. Furthermore, the B cells found in the infected meninges produced high-affinity autoantibodies able to recognise mouse brain antigens, in a process dependent on LTβ signalling. A mid-throughput screening identified several host factors recognised by these autoantibodies, including myelin basic protein (MBP), coinciding with cortical demyelination and brain pathology. In humans, we identified the presence of autoreactive IgG antibodies in the cerebrospinal fluid (CSF) of second stage HAT patients that recognised human brain lysates and MBP, consistent with our findings in experimental infections. Lastly, we found that the pathological B cell responses we observed in the meninges required the presence of T. brucei in the CNS, as suramin treatment before the onset of the CNS stage prevented the accumulation of GL7+ CD95+ GC-like B cells and brain-specific autoantibody deposition. Taken together, our data provide evidence that the meningeal immune response during chronic T. brucei infection results in the acquisition of lymphoid tissue-like properties, broadening our understanding of meningeal immunity in the context of chronic infections. These findings have wider implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity in mice and humans, as observed in other autoimmune neurodegenerative disorders, including neuropsychiatric lupus and multiple sclerosis.
| Item Type: | Articles |
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| Additional Information: | Funding: This work was funded by a Sir Henry Wellcome postdoctoral fellowship (221640/Z/20/Z to JFQ). AML is a Wellcome Trust Senior Research fellow (209511/Z/17/Z). PC and MCS are supported by a Wellcome Trust Senior Research fellowship (209511/Z/17/Z) awarded to AML. DB is funded by an MRC fellowship MR/V009052/1 and a Lister Institute Fellowship. NAM is supported by project Institute Strategic Programme Grant funding from the BBSRC (BBS/E/D/20002174 and BB/X010937/1). LKD is funded by a Barts Charity Rising Star Program (MICG1E1R to LKD). Data Availability Statement: The transcriptome data generated in this study have been deposited in the Gene Expression Omnibus (GSE229436). The processed transcript count data and cell metadata generated in this study, as well as the code for analysis, are available at Zenodo (DOI: 10.5281/ zenodo.7814657 and https://zenodo.org/records/ 10018598). Additional data and files can also be sourced via Supplementary Tables. Code availability: The processed transcript count data and cell metadata generated in this study, as well as the code for analysis, are available at Zenodo (DOI: 10.5281/zenodo.7814657 and https:// zenodo.org/records/10018598). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Sinton, Dr Matthew and MacLeod, Professor Annette and Kuispond Swar, Nono-Raymond and Al Samman, Mr Moumen and Chandrasegaran, Miss Praveena and Ogunsola, Mr John and Quintana, Dr Juan |
| Creator Roles: | Quintana, J.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing Sinton, M.Formal analysis, Investigation, Methodology, Writing – review and editing Chandrasegaran, P.Formal analysis, Investigation, Methodology, Validation, Writing – review and editing Ogunsola, J.Investigation, Writing – review and editing Al Samman, M.Investigation, Validation Kuispond Swar, N.-R.Investigation MacLeod, A.Writing – review and editing |
| Authors: | Quintana, J. F., Sinton, M. C., Chandrasegaran, P., Dubey, L. K., Ogunsola, J., Al Samman, M., Haley, M., McConnell, G., Kuispond Swar, N.-R., Ngoyi, D. M., Bending, D., de Lecea, L., Macleod, A., and Mabbott, N. A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| Journal Name: | PLoS Biology |
| Publisher: | Public Library of Science |
| ISSN: | 1544-9173 |
| ISSN (Online): | 1545-7885 |
| Copyright Holders: | Copyright: © 2023 Quintana et al. |
| First Published: | First published in PLoS Biology 21(11): e3002389 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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