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APOLs with low pH dependence can kill all African trypanosomes

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Show simple item record Fontaine, F. en_US Lecordier, L. en_US Vanwalleghem, G. en_US Uzureau, P. en_US Van Reet, N. en_US Fontaine, M. en_US Tebabi, P. en_US Vanhollebeke, B. en_US Büscher, P. en_US Perez-Morga, D. en_US Pays, E. en_US 2017-12-18T12:55:40Z 2017-12-18T12:55:40Z 2017 en_US
dc.identifier.issn 2058-5276 en_US
dc.identifier.doi en_US
dc.identifier.other ITG-B5A; ITG-B9A; DBM; U-PARDIA; DOI; CPDF; Abstract; DSPACE64 en_US
dc.description.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.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. en_US
dc.language English en_US
dc.relation.uri en_US
dc.subject Trypanosoma en_US
dc.subject Protozoology en_US
dc.subject Treatment en_US
dc.subject APOL en_US
dc.title APOLs with low pH dependence can kill all African trypanosomes en_US
dc.type Article-P en_US
dc.citation.jtitle Nature Microbiology en_US
dc.citation.volume 2 en_US
dc.citation.pages 1500-1506 en_US
dc.citation.abbreviation Nat Microbiol en_US

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