Host-pathogen interactions in the mouse brain during chronic infection with African trypanosomes. Multi-omic approaches reveal distinct microglia-plasma cell crosstalk in the mouse brain during chronic Trypanosoma brucei infection

A major hallmark of human African trypanosomiasis (HAT), or sleeping sickness, is a profound reactivity of glial cells, termed gliosis, and neuroinflammation, leading to coma and death if left untreated. Additionally, sleep/wake patterns and circadian disturbances have also been extensively reported in sleeping sickness. However, the transcriptional and functional responses of the innate and adaptive immune system operating in the central nervous system (CNS) during chronic Trypanosoma brucei infection remain poorly understood. By integrating single cell RNA sequencing and spatial transcriptomics of the mouse brain, we identified that glial responses triggered by infection are not limited to the hypothalamus but can also be readily detected in the proximity to the circumventricular organs (CVOs), coinciding with the spatial localisation of both slender and stumpy forms of T. brucei. Furthermore, in silico predictions and functional validations lead us to identify a previously unknown bidirectional interaction between homeostatic Cx3cr1+ microglia and plasma cells mediated by IL-10 and B cell activating factor (BAFF) signalling. We propose a spatiotemporal atlas for disease progression during chronic infection, involving the interaction between cells of the adaptive immunity with stromal cells in the brain parenchyma and the CVOs. This study provides important insights and resources to improve understanding of the molecular and cellular responses triggered in the brain upon infection with African trypanosomes.