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Reference: Stijlemans, B, Caljon, G, Natesan, SK et al., (2011). High affinity nanobodies against the Trypanosome brucei VSG are potent trypanolytic agents that block endocytosis. PLoS pathogens, 7 (6), e1002072.Citable link to this page:

 

High affinity nanobodies against the Trypanosome brucei VSG are potent trypanolytic agents that block endocytosis.

Abstract: The African trypanosome Trypanosoma brucei, which persists within the bloodstream of the mammalian host, has evolved potent mechanisms for immune evasion. Specifically, antigenic variation of the variant-specific surface glycoprotein (VSG) and a highly active endocytosis and recycling of the surface coat efficiently delay killing mediated by anti-VSG antibodies. Consequently, conventional VSG-specific intact immunoglobulins are non-trypanocidal in the absence of complement. In sharp contrast, monovalent antigen-binding fragments, including 15 kDa nanobodies (Nb) derived from camelid heavy-chain antibodies (HCAbs) recognizing variant-specific VSG epitopes, efficiently lyse trypanosomes both in vitro and in vivo. This Nb-mediated lysis is preceded by very rapid immobilisation of the parasites, massive enlargement of the flagellar pocket and major blockade of endocytosis. This is accompanied by severe metabolic perturbations reflected by reduced intracellular ATP-levels and loss of mitochondrial membrane potential, culminating in cell death. Modification of anti-VSG Nbs through site-directed mutagenesis and by reconstitution into HCAbs, combined with unveiling of trypanolytic activity from intact immunoglobulins by papain proteolysis, demonstrates that the trypanolytic activity of Nbs and Fabs requires low molecular weight, monovalency and high affinity. We propose that the generation of low molecular weight VSG-specific trypanolytic nanobodies that impede endocytosis offers a new opportunity for developing novel trypanosomiasis therapeutics. In addition, these data suggest that the antigen-binding domain of an anti-microbial antibody harbours biological functionality that is latent in the intact immunoglobulin and is revealed only upon release of the antigen-binding fragment.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Publisher's version Funder: Vrije Universiteit Brussel   Funder: Flemisch institute for Biotechnology   Funder: Wellcome Trust   Notes:© 2011 Stijlemans et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Bibliographic Details

Publisher: Public Library of Science

Publisher Website: http://www.plos.org/

Journal: PLoS pathogenssee more from them

Publication Website: http://www.plospathogens.org/

Issue Date: 2011-6

pages:e1002072Identifiers

Urn: uuid:2966727d-13cb-4aed-b006-23a09b46ab84

Source identifier: 154798

Eissn: 1553-7374

Doi: https://doi.org/10.1371/journal.ppat.1002072

Issn: 1553-7366 Item Description

Type: Journal article;

Language: eng

Version: Publisher's versionKeywords: Animals Mice, Inbred C57BL Humans Mice Trypanosoma brucei brucei Cells, Cultured Trypanosomiasis, African Variant Surface Glycoproteins, Trypanosoma Antibodies, Protozoan Endocytosis Antibody Affinity Down-Regulation Amino Acid Sequence Molecular Sequence Data Trypanocidal Agents Models, Biological Models, Molecular Nanoparticles Tiny URL: pubs:154798

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Autor: Stijlemans, B - - - Caljon, G - - - Natesan, SK - - - Saerens, D - - - Conrath, K - - - Pérez-Morga, D - - - Skepper, JN - - - N

Fuente: https://ora.ox.ac.uk/objects/uuid:2966727d-13cb-4aed-b006-23a09b46ab84



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