Adaptive metabolic reprogramming of the brain tissue during late-stage Trypanosoma brucei infection maintains host...

Human African Trypanosomiasis (HAT) is a two-stage infection caused by Trypanosoma brucei ssp. In stage I the trypanosomes are in blood, lymph and tissue interstitial space and the infection progresses to stage II when the parasites enter the central nervous system (CNS), resulting in behavioural aberrations that proceed to coma and death. Here, we use a bioluminescent murine model of HAT to examine parasite localisation and the changes in host brain gene expression, metabolism and function, and behaviour that occur over the course of the infection. The murine HAT model reproduces the decrease in brain tryptophan well established in clinical samples, and we report for the first time an unprecedented 1.8-fold decrease in global brain glucose metabolism in stage II infection. These metabolic changes are accompanied by an 18-fold decrease in brain insulin transcripts without changes in pathways regulating the cellular responses to insulin. By contrast, genes involved in fatty acid and lipid metabolism are upregulated in the brain during stage II infection. Moreover, we show that transcriptional programmes regulating mitochondrial metabolism dynamically adapts across the time course of HAT infection, ultimately leading to a transcriptional programme that diverts host brain metabolism away from glycolysis during stage II infection. Overall, our data demonstrate a reprogramming of brain energy metabolism during stage II HAT infection that favours the utilization of fatty acids and lipids to meet the energy demands of the brain, with a reduced reliance on glucose metabolism. Despite the profound neurometabolic changes observed, host anxiety-like behaviour is unchanged and episodic learning and memory is not impaired, suggesting that brain metabolic reprogramming enables the utilisation of adipose reserves to maintain core brain functions. These finding may explain the progressive onset of neurological symptoms in HAT patients and inform the development therapeutic interventions to alleviate them.