Brain rewires energy metabolism to protect memory in late-stage sleeping sickness

Human African trypanosomiasis, caused by the parasite Trypanosoma brucei, unfolds in two stages. In stage I, trypanosomes circulate in the blood, lymph and tissue interstitial spaces. The infection progresses to stage II when the parasites invade the central nervous system, producing behavioural aberrations that can proceed to coma and death. Using a bioluminescent murine model of the disease, researchers tracked parasite localisation alongside changes in host brain gene expression, metabolism, function and behaviour over the course of infection, and found that the brain undergoes a striking metabolic reprogramming during late-stage disease rather than a simple collapse of function.

The model reproduced the decrease in brain tryptophan that is well established in clinical samples from patients. More notably, the study reports for the first time an unprecedented 1.8-fold decrease in global brain glucose metabolism during stage II infection. This shift away from glucose was accompanied by an 18-fold decrease in brain insulin transcripts, although the pathways regulating the cellular responses to insulin were unchanged. By contrast, genes involved in fatty acid and lipid metabolism were upregulated in the brain during stage II, pointing to an alternative fuel supply being recruited.

Transcriptional programmes regulating mitochondrial metabolism were shown to adapt dynamically across the time course of infection, ultimately producing a programme that diverts host brain metabolism away from glycolysis during stage II. Taken together, the data demonstrate a reprogramming of brain energy metabolism that favours the utilisation of fatty acids and lipids to meet the brain’s energy demands, with a reduced reliance on glucose. The authors suggest this enables the brain to draw on adipose reserves to maintain core functions while glucose metabolism is suppressed.

Despite these profound neurometabolic changes, host anxiety-like behaviour was unchanged and episodic learning and memory were not impaired in the infected animals. The researchers propose that this metabolic reprogramming may explain the progressive onset of neurological symptoms in HAT patients, and that understanding the switch could inform the development of therapeutic interventions to alleviate those symptoms. The findings come from a murine model, so their translation to human disease will require further validation.

Subject of Research: Brain metabolic reprogramming during late-stage Trypanosoma brucei infection in a murine model of human African trypanosomiasis

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

Article References: Fathallah, N., Barnes, C., Chatwin, R., Whittingham-Dowd, J., Worthington, J. J., Jackson-Jones, L., Dawson, N., & Urbaniak, M. D. (2026). Adaptive metabolic reprogramming of the brain tissue during late-stage Trypanosoma brucei infection maintains host learning and memory. PLOS Pathogens, 22(10), e1014734. https://doi.org/10.1371/journal.ppat.1014734

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014734

Keywords: Trypanosoma brucei, human African trypanosomiasis, sleeping sickness, brain metabolism, glucose metabolism, fatty acid metabolism, mitochondrial reprogramming, insulin transcripts, tryptophan, learning and memory, murine model, central nervous system