Localization of serum resistance-associated protein in<i>Trypanosoma brucei rhodesiense</i>and transgenic<i>Trypanosoma brucei brucei</i>

Bart, Jean-Mathieu; Cordon-Obras, Carlos; Ferreirós-Vidal, Isabel; Reed, Jennifer; Pérez-Pastrana, Esperanza; Cuevas, Laureano; Field, Mark C.; Carrington, Mark; Navarro, Miguel

doi:10.1111/cmi.12454

Cited by 13 publications

(7 citation statements)

References 31 publications

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“…The major surface glycoproteins are also distinct, and although the functions of many of these glycoproteins remain unknown, they likely are crucial for survival in the host [56]. Furthermore, the endosomal apparatus contains some components that are important for defence against the innate immune response [57]. All of these peculiarities offer the potential for therapeutic exploitation.…”

Section: Target-based Approachesmentioning

confidence: 99%

Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need

et al. 2017

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The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addition, we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.

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Section: Target-based Approachesmentioning

confidence: 99%

Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need

et al. 2017

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“…p2T7TiCLH transfected cells were selected with 2.5 μg mL −1 G418 and 5 μg mL −1 Hygromycin. Clones were induced with 5 μg mL −1 doxycycline and selected for growth defect and human transferrin (HT) uptake decrease ( Bart et al, 2015 ). The effect of AS-48 on the growth was performed in triplicate with cells induced for 4 h.…”

Section: Methodsmentioning

confidence: 99%

Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48

Martínez‐García

Bart

Campos‐Salinas

et al. 2018

International Journal for Parasitology: Drugs and Drug Resistan

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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.

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“…b . rhodesiense , resistance is effected by the VSG-derived, serum resistance associated (SRA) protein [ 35 , 36 ] which binds to the C-terminal domain of APOL1 in the endolysosome pathway preventing channel-mediated lysis [ 27 , 37 – 39 ], plausibly by impeding correct membrane insertion of APOL1 [ 34 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

A Primate APOL1 Variant That Kills Trypanosoma brucei gambiense

et al. 2016

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Humans are protected against infection from most African trypanosomes by lipoprotein complexes present in serum that contain the trypanolytic pore-forming protein, Apolipoprotein L1 (APOL1). The human-infective trypanosomes, Trypanosoma brucei rhodesiense in East Africa and T. b. gambiense in West Africa have separately evolved mechanisms that allow them to resist APOL1-mediated lysis and cause human African trypanosomiasis, or sleeping sickness, in man. Recently, APOL1 variants were identified from a subset of Old World monkeys, that are able to lyse East African T. b. rhodesiense, by virtue of C-terminal polymorphisms in the APOL1 protein that hinder that parasite’s resistance mechanism. Such variants have been proposed as candidates for developing therapeutic alternatives to the unsatisfactory anti-trypanosomal drugs currently in use. Here we demonstrate the in vitro lytic ability of serum and purified recombinant protein of an APOL1 ortholog from the West African Guinea baboon (Papio papio), which is able to lyse examples of all sub-species of T. brucei including T. b. gambiense group 1 parasites, the most common agent of human African trypanosomiasis. The identification of a variant of APOL1 with trypanolytic ability for both human-infective T. brucei sub-species could be a candidate for universal APOL1-based therapeutic strategies, targeted against all pathogenic African trypanosomes.

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Localization of serum resistance-associated protein inTrypanosoma brucei rhodesienseand transgenicTrypanosoma brucei brucei

Cited by 13 publications

References 31 publications

Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need

Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need

Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48

A Primate APOL1 Variant That Kills Trypanosoma brucei gambiense

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