title: Mechanism of Trypanosoma brucei gambiense resistance to human serum.
abstract: 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 β-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.
authors: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 12 rue des Prof. Jeener et Brachet, B-6041 Gosselies, Belgium.
authors: Pierrick
authors: P
authors: Uzureau
authors: Sophie
authors: S
authors: Uzureau
authors: Laurence
authors: L
authors: Lecordier
authors: Frédéric
authors: F
authors: Fontaine
authors: Patricia
authors: P
authors: Tebabi
authors: Fabrice
authors: F
authors: Homblé
authors: Axelle
authors: A
authors: Grélard
authors: Vanessa
authors: V
authors: Zhendre
authors: Derek P
authors: DP
authors: Nolan
authors: Laurence
authors: L
authors: Lins
authors: Jean-Marc
authors: JM
authors: Crowet
authors: Annette
authors: A
authors: Pays
authors: Cécile
authors: C
authors: Felu
authors: Philippe
authors: P
authors: Poelvoorde
authors: Benoit
authors: B
authors: Vanhollebeke
authors: Soren K
authors: SK
authors: Moestrup
authors: Jeppe
authors: J
authors: Lyngsø
authors: Jan Skov
authors: JS
authors: Pedersen
authors: Jeremy C
authors: JC
authors: Mottram
authors: Erick J
authors: EJ
authors: Dufourc
authors: David
authors: D
authors: Pérez-Morga
authors: Etienne
authors: E
authors: Pays
mesh_terms: D000349:Africa; D000818:Animals; D030801:Animals, Genetically Modified; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000037:antagonists & inhibitors / Q000097:blood* / Q000378:metabolism* / Q000633:toxicity; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D057056:Cysteine Proteases / Q000378:metabolism; D006242:Haptoglobins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000037:antagonists & inhibitors / Q000097:blood* / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D010271:Parasites / Q000472:pathogenicity / Q000502:physiology; D017433:Protein Structure, Secondary; D044967:Serum / Q000737:chemistry / Q000469:parasitology; D014347:Trypanosoma brucei gambiense / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D014353:Trypanosomiasis, African / Q000469:parasitology; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000737:chemistry / Q000378:metabolism
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D006242:Haptoglobins; D006454:Hemoglobins; D008075:Lipoproteins, HDL; C434063:TLF1 protein, human; D014643:Variant Surface Glycoproteins, Trypanosoma; D057056:Cysteine Proteases
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