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APOLs with low pH dependence can kill all African trypanosomes

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  • Frédéric Fontaine, Université Libre de Bruxelles
  • ,
  • Laurence Lecordier, Université Libre de Bruxelles
  • ,
  • Gilles Vanwalleghem
  • Pierrick Uzureau, Université Libre de Bruxelles
  • ,
  • Nick Van Reet, Institute of Tropical Medicine Antwerp
  • ,
  • Martina Fontaine, Université Libre de Bruxelles
  • ,
  • Patricia Tebabi, Université Libre de Bruxelles
  • ,
  • Benoit Vanhollebeke, Université Libre de Bruxelles
  • ,
  • Philippe Büscher, Institute of Tropical Medicine Antwerp
  • ,
  • David Pérez-Morga, Université Libre de Bruxelles
  • ,
  • Etienne Pays, Université Libre de Bruxelles

The primate-specific serum protein apolipoprotein L1 (APOL1) is the only secreted member of a family of cell death promoting proteins 1-4 . APOL1 kills the bloodstream parasite Trypanosoma brucei brucei, but not the human sleeping sickness agents T.b. rhodesiense and T.b. gambiense 3 . We considered the possibility that intracellular members of the APOL1 family, against which extracellular trypanosomes could not have evolved resistance, could kill pathogenic T. brucei subspecies. Here we show that recombinant APOL3 (rAPOL3) kills all African trypanosomes, including T.b. rhodesiense, T.b. gambiense and the animal pathogens Trypanosoma evansi, Trypanosoma congolense and Trypanosoma vivax. However, rAPOL3 did not kill more distant trypanosomes such as Trypanosoma theileri or Trypanosoma cruzi. This trypanolytic potential was partially shared by rAPOL1 from Papio papio (rPpAPOL1). The differential killing ability of rAPOL3 and rAPOL1 was associated with a distinct dependence on acidic pH for activity. Due both to its instability and toxicity when injected into mice, rAPOL3 cannot be used for the treatment of infection, but an experimental rPpAPOL1 mutant inspired by APOL3 exhibited enhanced trypanolytic activity in vitro and the ability to completely inhibit T.b. gambiense infection in mice. We conclude that pH dependence influences the trypanolytic potential of rAPOLs.

Original languageEnglish
JournalNature Microbiology
Volume2
Issue11
Pages (from-to)1500-1506
Number of pages7
ISSN2058-5276
DOIs
Publication statusPublished - 1 Nov 2017
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank A. Kremer (Ghent) for the FIB–SEM acquisitions. This work was supported by the European Research Council (ERC 669007-APOLs), the Interuniversity Attraction Poles Programme–Belgian Science Policy (PAI P7-41) and the PDR-FNRS (PDR T.0159.13). The Center for Microscopy and Molecular Imaging is supported by the European Regional Development Fund and Wallonia.

Publisher Copyright:
© 2017 The Author(s).

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