Journal Article

APOLs with low pH dependence can kill all African trypanosomes

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

2017

Overview

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 (r Pp APOL1). 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 r Pp APOL1 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. Recombinant proteins based on APOL1 and APOL3 can kill pathogenic Trypanosoma brucei subspecies, including a variant (rPpMUT) that is effective against T.b. gambiense infection in mice, suggesting that it may serve as a therapy against sleeping sickness.

• Publisher: Nature Publishing Group UK
• Subject: 631/326/22/1294 / 631/326/417/2546 / 631/326/421 / Animals / Apolipoprotein L1 - genetics / Apolipoprotein L1 - pharmacology / Apolipoproteins L - genetics / Apolipoproteins L - pharmacology / Biomedical and Life Sciences / Hydrogen-Ion Concentration / Infectious Diseases / Letter / Life Sciences / Medical Microbiology / Mice / Microbiology / Papio papio / Parasitology / Protozoan Proteins - metabolism / Recombinant Proteins - pharmacology / Trypanosoma - drug effects / Trypanosoma - physiology / Trypanosoma brucei brucei - drug effects / Trypanosoma brucei gambiense - drug effects / Trypanosoma brucei rhodesiense - drug effects / Trypanosoma congolense - drug effects / Trypanosoma vivax - drug effects / Trypanosomiasis, African - parasitology / Virology