APOLs with low pH dependence can kill all African trypanosomes

The primate-specific serum protein apolipoprotein L1 (APOL1) is the only secreted member of a family of cell death promoting proteins1–4. APOL1 kills the bloodstream parasite Trypanosoma brucei brucei, but not the human sleeping sickness agents T.b. rhodesiense and T.b. gambiense3. 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 T. evansi, T. congolense and T. vivax. In contrast, rAPOL3 did not kill more distant trypanosomes such as T. theileri or T. cruzi. This trypanolytic potential was partially shared by rAPOL1 from Papio papio (rPpAPOL1). The differential killing ability between rAPOL3 and rAPOL1 was associated with distinct dependence on acidic pH for activity. Due to both instability and toxicity when injected into mice rAPOL3 cannot be used for treatment of infection, but an experimental rPpAPOL1 mutant inspired by APOL3 exhibited enhanced trypanolytic activity in vitro and ability to completely inhibit T.b. gambiense infection in mice. We conclude that pH dependence influences the trypanolytic potential of rAPOLs.