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Apolipoprotein L-I is the trypanosome lytic factor of human serum

Abstract

Human sleeping sickness in east Africa is caused by the parasite Trypanosoma brucei rhodesiense. The basis of this pathology is the resistance of these parasites to lysis by normal human serum (NHS)1,2. Resistance to NHS is conferred by a gene that encodes a truncated form of the variant surface glycoprotein termed serum resistance associated protein (SRA)3,4. We show that SRA is a lysosomal protein, and that the amino-terminal α-helix of SRA is responsible for resistance to NHS. This domain interacts strongly with a carboxy-terminal α-helix of the human-specific serum protein apolipoprotein L-I (apoL-I). Depleting NHS of apoL-I, by incubation with SRA or anti-apoL-I, led to the complete loss of trypanolytic activity. Addition of native or recombinant apoL-I either to apoL-I-depleted NHS or to fetal calf serum induced lysis of NHS-sensitive, but not NHS-resistant, trypanosomes. Confocal microscopy demonstrated that apoL-I is taken up through the endocytic pathway into the lysosome. We propose that apoL-I is the trypanosome lytic factor of NHS, and that SRA confers resistance to lysis by interaction with apoL-I in the lysosome.

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Figure 1: Expression of SRA and phenotype of pTSARib-transfected T. b. brucei.
Figure 2: Localization of SRA and apoL-I in the T. b. rhodesiense ETat 1.2R clone.
Figure 3: Binding of apoL-I to SRA.
Figure 4: Lytic activity of apoL-I.

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Acknowledgements

We thank M. Chamekh for the pQ30-SRA plasmid, A. Michel and V. Stroobant for peptide synthesis, S. Kler and C. Flore for technical assistance, and D. Perez-Morza and S. Schurmans for help. This work was supported by the Belgian Fund for Scientific Research (FRSM, FWO and Crédit aux Chercheurs) and by the Interuniversity Attraction Poles Programme, Belgian State, Federal Office for Scientific, Technical and Cultural Affairs. R.B., L.V. and L.L. are, respectively, Research Director and Research Associates at the Belgian Fund for Scientific Research.

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Correspondence to Etienne Pays.

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Vanhamme, L., Paturiaux-Hanocq, F., Poelvoorde, P. et al. Apolipoprotein L-I is the trypanosome lytic factor of human serum. Nature 422, 83–87 (2003). https://doi.org/10.1038/nature01461

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