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The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronic Trypanosoma brucei infection

ABSTRACT: The meningeal space is an important structure in the brain borders, which provides immunosurveillance for the central nervous system, but the impact of infections on the meningeal immune landscape is far from being fully understood. Trypanosoma brucei, the causative agents of Human African Trypanosomiasis or sleeping sickness, accumulates in the meningeal spaces, 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, combining single cell transcriptomics and mass cytometry by time of flight (CyTOF), coupled with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges during chronic infection. These infection-induced ectopic structures are defined by the presence of ER-TR7+ fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) that initiate a signalling cascade driving local T cell activation towards a T follicular helper (TFH)-like phenotype, as well as B cell class switching. Furthermore, the meningeal-resident plasma cells display activity typically associated with germinal centre reactions and are able to produce antibodies able to recognise mouse brain antigens, which correlates with cortical (and white matter) demyelination. Lastly, we found that systemic lymphotoxin (LT) signalling blockade led to a significant depletion of meningeal FDCs and autoreactive B cells, indicating that LTsignalling is critical to induce and maintain local responses in the meninges. Taken together, we provide evidence that the meningeal immune response results in the acquisition of lymphoid tissue-like properties during chronic T. brucei infection. These findings have broader implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity, as observed in other demyelinating neurodegenerative disorders such as multiple sclerosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE229436 | GEO | 2023/10/26

REPOSITORIES: GEO

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Project description:Approximately 20% of sleeping sickness patients exhibit respiratory complications which are commonly attributed to secondary bacterial infections, with an unknown role of the parasite. Using a Glossina morsitans tsetse fly initiated Trypansoma brucei infection in mice we found that parasites rapidly and permanently colonize the lungs, representing one of the major target organs next to the adipose tissue. Trypanosomes were found by immunofluorescence staining and scanning electron microscopy to occupy the extravascular spaces surrounding the blood vessels of the alveoli and bronchi. Parasites were even found in the lung cartilage. Trypanosomes were often observed as nests of multiplying parasites exhibiting close interactions with collagen and highly active secretion of extracellular vesicles that are engaged in intercellular communication. The local immune response was analysed by flow cytometry after 10 and 21 days of infection and was characterized by a substantial increase of CD11b+ Ly6C+ monocytes, CD11b+ Ly6C+ F4/80+ macrophages and CD11b+ CD11c+ dendritic cells. CD11b+ Ly6G+ neutrophils only accumulated prominently at the late infection time point. Interestingly, parasite presence resulted in a significant reduction of B220+ IgM+ B cells, CD11b+ CD11clo/- SiglecF+ eosinophils and TcR-β- NK1.1+ natural killer cells. Digital transcriptomics revealed infection-induced upregulation of Il-10, IFN-ɣ- and IFN-α-responses, IL-2-, IL-6- and TNF-signalling, a Th1 pro-inflammatory signature, negative immune checkpoint regulators and a predominant M1 macrophage polarization. Il12a and genes associated with complement and the B cell receptor were downregulated. No infection-associated pulmonary dysfunction could be detected by in vivo lung function measurements, mirroring the limited pulmonary complications during sleeping sickness. However, the substantial reduction of eosinophils, B cells and NK cells may render individuals more susceptible to opportunistic infections. Collectively, these observations provide essential insights in the peculiar parasite biology, immunological reactions and physiological function of a largely overlooked target organ which may trigger new diagnostic approaches for sleeping sickness.

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The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronic Trypanosoma brucei infection

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