Abstract
Trypanosoma brucei is the causative agent of African sleeping sickness. Available treatments are ineffective, toxic and susceptible to resistance by the parasite. Here we show that various endogenous neuropeptides act as potent antitrypanosome agents. Neuropeptides exerted their trypanolytic activity through an unusual mechanism that involves peptide uptake by the parasite, disruption of lysosome integrity and cytosolic accumulation of glycolytic enzymes. This promotes an energetic metabolism failure that initiates an autophagic-like cell death. Neuropeptide-based treatment improved clinical signs in a chronic model of trypanosomiasis by reducing the parasite burden in various target organs. Of physiological importance is the fact that hosts respond to trypanosome infection producing neuropeptides as part of their natural innate defense. From a therapeutic point of view, targeting of intracellular compartments by neuropeptides suppose a new promising strategy for the treatment of trypanosomiasis.
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Abbreviations
- AM:
-
adrenomedullin
- apo-L1:
-
apolipoprotein-1
- BSF:
-
bloodstream forms
- FAM:
-
carboxifluorescein
- PCF:
-
procyclic forms
- PGK:
-
phosphoglycerate kinase
- UCN:
-
urocortin
- VIP:
-
vasoactive intestinal peptide
- VSG:
-
variant surface glycoprotein
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Acknowledgements
We thank PA Michels and V Hannaert (Université Catholique de Louvain) and JD Bangs (University of Wisconsin Medical School) for providing invaluable antibodies for glycosome and lysosomal proteins. This study was supported by Spanish Ministry of Education and Science, FIS and RETICS.
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Supplementary Information accompanies the paper on Cell Death and Differentiation website (http://www.nature.com/cdd)
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Delgado, M., Anderson, P., Garcia-Salcedo, J. et al. Neuropeptides kill African trypanosomes by targeting intracellular compartments and inducing autophagic-like cell death. Cell Death Differ 16, 406–416 (2009). https://doi.org/10.1038/cdd.2008.161
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DOI: https://doi.org/10.1038/cdd.2008.161
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