APOLs with low pH dependence can kill all African trypanosomes

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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Fig. 1: In vitro trypanolytic potential of various rAPOLs.
Fig. 2: Phenotype of rAPOL3-mediated trypanolysis.
Fig. 3: Differential pH dependence of rAPOL3, rAPOL1 and rPpAPOL1.
Fig. 4: In vivo trypanolytic potential of various 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.

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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.

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Correspondence to Etienne Pays.

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Fontaine, F., Lecordier, L., Vanwalleghem, G. et al. APOLs with low pH dependence can kill all African trypanosomes. Nat Microbiol 2, 1500–1506 (2017). https://doi.org/10.1038/s41564-017-0034-1

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