Authors

Discussion

Chronic infection with Trypanosoma brucei, the causative agent of Human African trypanosomiasis (HAT), induces gliosis and neuroinflammation in the central nervous system (CNS). Disease outcome varies greatly depending on the parasite subspecies; rhodesiense HAT is considered more aggressive, whereas gambiense HAT often causes a milder, subclinical infection. In this study, we used single cell transcriptomics to investigate CNS responses in murine models of infection with trypanosome causing subclinical or clinical infections (T. b. gambiense and T. b. brucei, respectively). We analysed ~20, 000 cells from the hypothalamus of naïve and infected mice and identified a total of 10 cell clusters with an ~500 genes/ cell and ~1,000 transcripts/cell, including microglia, astrocytes, vascular-associated cells, T and B cells. Of these, B cell with a regulatory phenotype (Ighm, Cd79a, Cd79b, Il10) and microglia with a robust pro-inflammatory phenotype (Il1a, Tgfbr1, Ifngr1, Il6ra, Il10ra) were abundant in T. b. brucei infection compared to T. b. gambiense. These observations are consistent with a reduced gliosis and neuroinflammation in T. b. gambiense infections compared to T. b. brucei infections. Furthermore, T. b. gambiense infection induces a progressive change in circadian activity without changes in clinical scoring, whereas T. b. brucei infection induces clinical symptoms that precedes changes in circadian behaviour. Taken together, our data suggest that changes in circadian behaviour in T. b. gambiense infection may arise due to low-grade CNS inflammation. Given the lack of clinical symptoms and based on the transcriptional and behavioural findings presented here, we propose that infection with T. b. gambiense is an ideal model to study how trypanosomes interfere with circadian rhythms without the need for pharmacological interventions. Our work provides important insights into mechanisms underlying the immunological responses of the CNS to different parasite subspecies, opening new avenues to investigate the molecular basis of HAT-associated circadian disorders.