APOLs with low pH dependence can kill all African trypanosomes

Frédéric Fontaine, Laurence Lecordier, Gilles Vanwalleghem, Pierrick Uzureau, Nick Van Reet, Martina Fontaine, Patricia Tebabi, Benoit Vanhollebeke, Philippe Büscher, David Pérez-Morga, Etienne Pays

    Research output: Contribution to journalA1: Web of Science-article

    Abstract

    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
    Issue number11
    Pages (from-to)1500-1506
    Number of pages7
    ISSN2058-5276
    DOIs
    Publication statusPublished - 2017

    Keywords

    • Journal Article

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