Publication Date:
2013-08-24
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Uzureau, Pierrick -- Uzureau, Sophie -- Lecordier, Laurence -- Fontaine, Frederic -- Tebabi, Patricia -- Homble, Fabrice -- Grelard, Axelle -- Zhendre, Vanessa -- Nolan, Derek P -- Lins, Laurence -- Crowet, Jean-Marc -- Pays, Annette -- Felu, Cecile -- Poelvoorde, Philippe -- Vanhollebeke, Benoit -- Moestrup, Soren K -- Lyngso, Jeppe -- Pedersen, Jan Skov -- Mottram, Jeremy C -- Dufourc, Erick J -- Perez-Morga, David -- Pays, Etienne -- 085349/Wellcome Trust/United Kingdom -- England -- Nature. 2013 Sep 19;501(7467):430-4. doi: 10.1038/nature12516. Epub 2013 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Parasitology, IBMM, Universite Libre de Bruxelles, 12 rue des Prof. Jeener et Brachet, B-6041 Gosselies, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23965626" target="_blank"〉PubMed〈/a〉
Keywords:
Africa
;
Animals
;
Animals, Genetically Modified
;
Apolipoproteins/antagonists & inhibitors/*blood/*metabolism/toxicity
;
Cell Membrane/chemistry/metabolism
;
Cysteine Proteases/metabolism
;
Haptoglobins/metabolism
;
Hemoglobins/metabolism
;
Hemolysis
;
Humans
;
Hydrophobic and Hydrophilic Interactions
;
Lipid Metabolism
;
Lipoproteins, HDL/antagonists & inhibitors/*blood/chemistry/*metabolism/toxicity
;
Parasites/pathogenicity/physiology
;
Protein Structure, Secondary
;
Serum/chemistry/parasitology
;
Trypanosoma brucei gambiense/drug effects/pathogenicity/*physiology
;
Trypanosomiasis, African/parasitology
;
Variant Surface Glycoproteins, Trypanosoma/chemistry/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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