Abstract

The primate-specific serum protein apolipoprotein L1 (APOL1) is the only secreted member of a family of cell death promoting proteins1,2,3,4. 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.

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Acknowledgements

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.

Author information

Author notes

    • Gilles Vanwalleghem

    Present address: School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, 4072, Australia

    • Pierrick Uzureau

    Present address: Laboratoire de Médecine Expérimentale (ULB222), Hôpital André Vésale, Université Libre de Bruxelles, 706, route de Gozée, B-6110, Montigny le Tilleul, Belgium

  1. Frédéric Fontaine and Laurence Lecordier contributed equally to this work.

Affiliations

  1. Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 12, rue des Profs Jeener et Brachet, B-6041, Gosselies, Belgium

    • Frédéric Fontaine
    • , Laurence Lecordier
    • , Gilles Vanwalleghem
    • , Pierrick Uzureau
    • , Patricia Tebabi
    • , Benoit Vanhollebeke
    • , David Pérez-Morga
    •  & Etienne Pays
  2. Unit of Parasite Diagnostics, Institute of Tropical Medicine, 155, Nationalestraat, B-2000, Antwerpen, Belgium

    • Nick Van Reet
    •  & Philippe Büscher
  3. Laboratory of Immunobiology, IBMM, Université Libre de Bruxelles, 12, rue des Profs Jeener et Brachet, B-6041, Gosselies, Belgium

    • Martina Fontaine
  4. Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, 12, rue des Profs Jeener et Brachet, B-6041, Gosselies, Belgium

    • David Pérez-Morga

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Contributions

E.P., F.F. and D.P.M. designed the research. F.F., L.L., G.V., P.U., M.S. and P.T. performed the research. B.V. supervised some experiments. N.V.R. and P.B. adapted the trypanosome strains to in vitro growth. E.P. and F.F. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Etienne Pays.

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DOI

https://doi.org/10.1038/s41564-017-0034-1