The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronicTrypanosoma bruceiinfection

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. The extracellular protozoan parasite Trypanosoma brucei, which causes Human African Trypanosomiasis (HAT) or sleeping sickness, accumulate 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, 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 GC-like B cells found in the infected meninges produce high-affinity autoantibodies able to recognise mouse brain antigens. We found that systemic lymphotoxin β (LTβ) signalling blockade led to a significant depletion of meningeal FDC-like cells and autoreactive B cells, indicating that LTβ signalling is critical to induce and maintain local responses in the meninges. In humans, we identified the presence of autoreactive IgG antibodies able to recognise human brain lysates in the cerebrospinal fluid of second stage HAT patients compared to first stage HAT patients, consistent with our findings in experimental infections. Taken together, our data provide evidence that the meningeal immune response results in the acquisition of lymphoid tissue-like properties during chronic T. brucei infection, 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 such as neuropsychiatric lupus and multiple sclerosis.

A murine model ofTrypanosoma brucei-induced myocarditis and cardiac dysfunction

“…Moreover, this suggests that immunomodulatory therapies could be considered for treatment of both humans and cattle to suppress inflammation that could contribute to persistent heart disease. There is a necessity to investigate the long-term and post-treatment consequences of T. brucei -associated myocarditis to determine whether HAT patients are at increased lifetime risk of heart failure 29,46…”

“…This hypothesis is corroborated by other evidence suggesting that T. brucei -associated organ damage has an auto-immune component. A recent study found that meningeal B cells produce high-affinity autoantibodies during T. brucei infection, suggesting that autoimmune responses may be a component of T. brucei -associated pathology in multiple tissues 46 . Clinically, cardiomyopathy patients in Cameroon have been found to have high levels of both anti-trypanosomal and anti-heart antibodies, further indicating a connection between T. brucei infection and autoimmune heart disease 16 .…”

“…Moreover, this suggests that immunomodulatory therapies could be considered for treatment of both humans and cattle to suppress inflammation that could contribute to persistent heart disease. There is a necessity to investigate the long-term and post-treatment consequences of T. brucei-associated myocarditis to determine whether HAT patients are at increased lifetime risk of heart failure 29,46 In summary, we describe the first reproducible, optimized, clinically relevant murine model of T. brucei-associated cardiac disease, a feature of African trypanosomiasis that is often overlooked in current textbooks and clinical resources 53,54 . In the context of this model's characterization, we produced evidence suggesting that T. brucei-associated cardiac damage is an immunemediated event.…”