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Mechanism of Trypanosoma brucei gambiense resistance to human serum.
- Source :
-
Nature [Nature] 2013 Sep 19; Vol. 501 (7467), pp. 430-4. Date of Electronic Publication: 2013 Aug 21. - Publication Year :
- 2013
-
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.
- Subjects :
- Africa
Animals
Animals, Genetically Modified
Apolipoprotein L1
Apolipoproteins antagonists & inhibitors
Apolipoproteins toxicity
Cell Membrane chemistry
Cell Membrane metabolism
Cysteine Proteases metabolism
Haptoglobins metabolism
Hemoglobins metabolism
Hemolysis
Humans
Hydrophobic and Hydrophilic Interactions
Lipid Metabolism
Lipoproteins, HDL antagonists & inhibitors
Lipoproteins, HDL chemistry
Lipoproteins, HDL toxicity
Parasites pathogenicity
Parasites physiology
Protein Structure, Secondary
Serum chemistry
Serum parasitology
Trypanosoma brucei gambiense drug effects
Trypanosoma brucei gambiense pathogenicity
Trypanosomiasis, African parasitology
Variant Surface Glycoproteins, Trypanosoma chemistry
Variant Surface Glycoproteins, Trypanosoma metabolism
Apolipoproteins blood
Apolipoproteins metabolism
Lipoproteins, HDL blood
Lipoproteins, HDL metabolism
Trypanosoma brucei gambiense physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 501
- Issue :
- 7467
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 23965626
- Full Text :
- https://doi.org/10.1038/nature12516