Mechanism of Trypanosoma brucei gambiense resistance to human serum.

[en] The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. 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). 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 membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic beta-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), 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 Africa.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Uzureau, Pierrick

Uzureau, Sophie

Lecordier, Laurence

Fontaine, Frederic

Tebabi, Patricia

Homble, Fabrice

Grelard, Axelle

Zhendre, Vanessa

Nolan, Derek P.

Lins, Laurence ; Université de Liège - ULiège > Chimie et bio-industries > Biophysique moléc. numér.

More authors (12 more)

Language :

English

Title :

Mechanism of Trypanosoma brucei gambiense resistance to human serum.

Publication date :

2013

Journal title :

Nature

ISSN :

0028-0836

eISSN :

1476-4687

Publisher :

Nature Publishing Group, London, United Kingdom

Volume :

501

Issue :

7467

Pages :

430-4

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 24 October 2013

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