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Mechanism of Trypanosoma brucei gambiense resistance to human serum

Abstract

The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases1. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1)2,3,4. Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes2,6,7. Here we report that T. b. gambiense resists TLFs via a hydrophobic β-sheet of the T. b. gambiense-specific glycoprotein (TgsGP)8, which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa9.

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Figure 1: TgsGP-mediated resistance to NHS.
Figure 2: TgsGP component responsible for resistance to NHS.
Figure 3: Activity of r-TgsGP and synthetic TgsGP peptides.
Figure 4: Features linked to T. b. gambiense resistance to NHS.

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Acknowledgements

We thank M. Prévost for advice, C. Giroud and T. Baltz for help with T. b. gambiense culture adaptation, D. Horn for the gift of pTMF plasmid and E. Dupont for technical assistance. This work was supported by the Belgian Fund for Scientific Research, the Walloon WELBIO excellence programme, the Interuniversity Attraction Poles Programme–Belgian Science Policy, and the ERC grant 233312 TROJA. The CMMI is supported by the European Regional Development Fund and the Walloon Region. Financial support from the TGIR-RMN-THC Fr3050 (French high-field NMR network) and the Welcome Trust is also acknowledged.

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P.U. and E.P. conceived the work; P.U., S.U., L.L., F.F., P.T., F.H., A.G., V.Z., D.P.N., L.L., J.-M.C., A.P., C.F., P.P., B.V., S.K.M., J.L., J.S.P. and D.P.-M. performed experiments; J.C.M. provided ICP knockout parasites; P.U., E.J.D., D.P.-M. and E.P. supervised different aspects of the experimental plan; P.U. and E.P. wrote the paper.

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Correspondence to Etienne Pays.

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Uzureau, P., Uzureau, S., Lecordier, L. et al. Mechanism of Trypanosoma brucei gambiense resistance to human serum. Nature 501, 430–434 (2013). https://doi.org/10.1038/nature12516

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