RESUMEN
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 ß-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.
Asunto(s)
Apolipoproteínas/sangre , Apolipoproteínas/metabolismo , Lipoproteínas HDL/sangre , Lipoproteínas HDL/metabolismo , Trypanosoma brucei gambiense/fisiología , África , Animales , Animales Modificados Genéticamente , Apolipoproteína L1 , Apolipoproteínas/antagonistas & inhibidores , Apolipoproteínas/toxicidad , Membrana Celular/química , Membrana Celular/metabolismo , Proteasas de Cisteína/metabolismo , Haptoglobinas/metabolismo , Hemoglobinas/metabolismo , Hemólisis , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Metabolismo de los Lípidos , Lipoproteínas HDL/antagonistas & inhibidores , Lipoproteínas HDL/química , Lipoproteínas HDL/toxicidad , Parásitos/patogenicidad , Parásitos/fisiología , Estructura Secundaria de Proteína , Suero/química , Suero/parasitología , Trypanosoma brucei gambiense/efectos de los fármacos , Trypanosoma brucei gambiense/patogenicidad , Tripanosomiasis Africana/parasitología , Glicoproteínas Variantes de Superficie de Trypanosoma/química , Glicoproteínas Variantes de Superficie de Trypanosoma/metabolismoRESUMEN
We have previously identified TGSGP as a gene specific to the Trypanosoma brucei gambiense subspecies. TGSGP is a truncated VSG-like telomeric gene transcribed by RNA polymerase II. The TGSGP protein localizes to the flagellar pocket, and exhibits features compatible with a role as surface receptor. Here we show that TGSGP is physically linked to a truncation of a gene homologous to yeast AUT1 (APG3), a gene involved in internal vesicular formation. Further analysis indicated that T. b. gambiense is heterozygous for AUT1 (AUT1/aut1), with each allele located on independent chromosome II homologues. In 18 T. b. gambiense isolates from distinct geographical origins and different hosts, this genomic rearrangement was conserved. The size of the intergenic region between TGSGP and truncated aut1 varied among isolates but was similar in isolates of the same geographical area, and this observation may be used in epidemiology to trace the geographical origin of T. b. gambiense isolates.