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

Abstract

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 seen 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. Author SummaryHuman African Trypanosomiasis is classically characterised as being a two-stage infection, stage I where the extracellular Trypanosoma brucei multiply in the blood, lymph and peripheral tissues, and stage II where parasite cross the blood-brain barrier (BBB) causing neurological symptoms and eventually death. Using a murine model of HAT we show that in stage II the key brain metabolite tryptophan is depleted and cerebral glucose utilisation is decreased, accompanied by extensive metabolic transcriptome reprogramming of the cerebral tissue during stage II infection. Despite this we see no significant change in mouse anxiety-like behaviour or learning and memory. Our data are consistent with the brain switching from glucose as the primary energy source, instead utilising the products of lipolysis to maintain essential brain functions. This new understanding of the neurometabolic changes that occur in stage II HAT may help to develop new treatments for the neurological symptoms that affect patients at this stage of the disease.