Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48
The parasitic protozoan Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) and nagana. Current drug therapies have limited efficacy, high toxicity and/or are continually hampered by the appearance of resistance. Antimicrobial peptides have recently attract...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-08-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320717301124 |
| _version_ | 1818411760518955008 |
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| author | Marta Martínez-García Jean-Mathieu Bart Jenny Campos-Salinas Eva Valdivia Manuel Martínez-Bueno Elena González-Rey Miguel Navarro Mercedes Maqueda Rubén Cebrián José M. Pérez-Victoria |
| author_facet | Marta Martínez-García Jean-Mathieu Bart Jenny Campos-Salinas Eva Valdivia Manuel Martínez-Bueno Elena González-Rey Miguel Navarro Mercedes Maqueda Rubén Cebrián José M. Pérez-Victoria |
| author_sort | Marta Martínez-García |
| collection | DOAJ |
| description | The parasitic protozoan Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) and nagana. Current drug therapies have limited efficacy, high toxicity and/or are continually hampered by the appearance of resistance. Antimicrobial peptides have recently attracted attention as potential parasiticidal compounds. Here, we explore circular bacteriocin AS-48's ability to kill clinically relevant bloodstream forms of T. brucei gambiense, T. brucei rhodesiense and T. brucei brucei. AS-48 exhibited excellent anti-trypanosomal activity in vitro (EC50 = 1–3 nM) against the three T. brucei subspecies, but it was innocuous to human cells at 104-fold higher concentrations. In contrast to its antibacterial action, AS-48 does not kill the parasite through plasma membrane permeabilization but by targeting intracellular compartments. This was evidenced by the fact that vital dye internalization-prohibiting concentrations of AS-48 could kill the parasite at 37 °C but not at 4 °C. Furthermore, AS-48 interacted with the surface of the parasite, at least in part via VSG, its uptake was temperature-dependent and clathrin-depleted cells were less permissive to the action of AS-48. The bacteriocin also caused the appearance of myelin-like structures and double-membrane autophagic vacuoles. These changes in the parasite's ultrastructure were confirmed by fluorescence microscopy as AS-48 induced the production of EGFP-ATG8.2-labeled autophagosomes. Collectively, these results indicate AS-48 kills the parasite through a mechanism involving clathrin-mediated endocytosis of VSG-bound AS-48 and the induction of autophagic-like cell death. As AS-48 has greater in vitro activity than the drugs currently used to treat T. brucei infection and does not present any signs of toxicity in mammalian cells, it could be an attractive lead compound for the treatment of sleeping sickness and nagana. Keywords: Trypanosoma brucei, Antimicrobial peptides, AS-48, Autophagy, Sleeping sickness, Trypanocidal drugs |
| first_indexed | 2024-12-14T10:36:32Z |
| format | Article |
| id | doaj.art-a9d8dcc8c8d542648626b8cfec12c250 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-12-14T10:36:32Z |
| publishDate | 2018-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-a9d8dcc8c8d542648626b8cfec12c2502022-12-21T23:05:53ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072018-08-0182203212Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48Marta Martínez-García0Jean-Mathieu Bart1Jenny Campos-Salinas2Eva Valdivia3Manuel Martínez-Bueno4Elena González-Rey5Miguel Navarro6Mercedes Maqueda7Rubén Cebrián8José M. Pérez-Victoria9Instituto de Parasitología y Biomedicina “López-Neyra”, CSIC (IPBLN-CSIC), PTS Granada, Granada, SpainCentro Nacional de Medicina Tropical, Instituto de Salud Carlos III, Madrid, Spain; UMR INTERTRYP, Institut de Recherche pour le Développement, Montpellier, FranceInstituto de Parasitología y Biomedicina “López-Neyra”, CSIC (IPBLN-CSIC), PTS Granada, Granada, SpainDepartamento de Microbiología, Facultad de Ciencias, Universidad de Granada, SpainDepartamento de Microbiología, Facultad de Ciencias, Universidad de Granada, SpainInstituto de Parasitología y Biomedicina “López-Neyra”, CSIC (IPBLN-CSIC), PTS Granada, Granada, SpainInstituto de Parasitología y Biomedicina “López-Neyra”, CSIC (IPBLN-CSIC), PTS Granada, Granada, SpainDepartamento de Microbiología, Facultad de Ciencias, Universidad de Granada, SpainDepartamento de Microbiología, Facultad de Ciencias, Universidad de Granada, Spain; Corresponding author.Instituto de Parasitología y Biomedicina “López-Neyra”, CSIC (IPBLN-CSIC), PTS Granada, Granada, Spain; Corresponding author.The parasitic protozoan Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) and nagana. Current drug therapies have limited efficacy, high toxicity and/or are continually hampered by the appearance of resistance. Antimicrobial peptides have recently attracted attention as potential parasiticidal compounds. Here, we explore circular bacteriocin AS-48's ability to kill clinically relevant bloodstream forms of T. brucei gambiense, T. brucei rhodesiense and T. brucei brucei. AS-48 exhibited excellent anti-trypanosomal activity in vitro (EC50 = 1–3 nM) against the three T. brucei subspecies, but it was innocuous to human cells at 104-fold higher concentrations. In contrast to its antibacterial action, AS-48 does not kill the parasite through plasma membrane permeabilization but by targeting intracellular compartments. This was evidenced by the fact that vital dye internalization-prohibiting concentrations of AS-48 could kill the parasite at 37 °C but not at 4 °C. Furthermore, AS-48 interacted with the surface of the parasite, at least in part via VSG, its uptake was temperature-dependent and clathrin-depleted cells were less permissive to the action of AS-48. The bacteriocin also caused the appearance of myelin-like structures and double-membrane autophagic vacuoles. These changes in the parasite's ultrastructure were confirmed by fluorescence microscopy as AS-48 induced the production of EGFP-ATG8.2-labeled autophagosomes. Collectively, these results indicate AS-48 kills the parasite through a mechanism involving clathrin-mediated endocytosis of VSG-bound AS-48 and the induction of autophagic-like cell death. As AS-48 has greater in vitro activity than the drugs currently used to treat T. brucei infection and does not present any signs of toxicity in mammalian cells, it could be an attractive lead compound for the treatment of sleeping sickness and nagana. Keywords: Trypanosoma brucei, Antimicrobial peptides, AS-48, Autophagy, Sleeping sickness, Trypanocidal drugshttp://www.sciencedirect.com/science/article/pii/S2211320717301124 |
| spellingShingle | Marta Martínez-García Jean-Mathieu Bart Jenny Campos-Salinas Eva Valdivia Manuel Martínez-Bueno Elena González-Rey Miguel Navarro Mercedes Maqueda Rubén Cebrián José M. Pérez-Victoria Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48 International Journal for Parasitology: Drugs and Drug Resistance |
| title | Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48 |
| title_full | Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48 |
| title_fullStr | Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48 |
| title_full_unstemmed | Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48 |
| title_short | Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48 |
| title_sort | autophagic related cell death of trypanosoma brucei induced by bacteriocin as 48 |
| url | http://www.sciencedirect.com/science/article/pii/S2211320717301124 |
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