title: Adaptation of Trypanosoma rhodesiense to hypohaptoglobinaemic serum requires transcription of the APOL1 resistance gene in a RNA polymerase I locus.
abstract: Human apolipoprotein L1 (APOL1) kills African trypanosomes except Trypanosoma rhodesiense and Trypanosoma gambiense, the parasites causing sleeping sickness. APOL1 uptake into trypanosomes is favoured by its association with the haptoglobin-related protein-haemoglobin complex, which binds to the parasite surface receptor for haptoglobin-haemoglobin. As haptoglobin-haemoglobin can saturate the receptor, APOL1 uptake is increased in haptoglobin-poor (hypohaptoglobinaemic) serum (HyHS). While T. rhodesiense resists APOL1 by RNA polymerase I (pol-I)-mediated expression of the serum resistance-associated (SRA) protein, T. gambiense resists by pol-II-mediated expression of the T. gambiense-specific glycoprotein (TgsGP). Moreover, in T. gambiense resistance to HyHS is linked to haptoglobin-haemoglobin receptor inactivation by mutation. We report that unlike T. gambiense, T. rhodesiense possesses a functional haptoglobin-haemoglobin receptor, and that like T. gambiense experimentally provided with active receptor, this parasite is killed in HyHS because of receptor-mediated APOL1 uptake. However, T. rhodesiense could adapt to low haptoglobin by increasing transcription of SRA. When assayed in Trypanosoma brucei, resistance to HyHS occurred with pol-I-, but not with pol-II-mediated SRA expression. Similarly, T. gambiense provided with active receptor acquired resistance to HyHS only when TgsGP was moved to a pol-I locus. Thus, transcription by pol-I favours adaptive gene regulation, explaining the presence of SRA in a pol-I locus.
authors.affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 12, rue des Profs Jeener et Brachet, B6041, Gosselies, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lecordier
authors.affiliation: Laboratoire de Médecine Expérimentale (ULB222), Hôpital André Vésale, Université Libre de Bruxelles, 706, route de Gozée, B6110, Montigny le Tilleul, Belgium.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Uzureau
authors.affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 12, rue des Profs Jeener et Brachet, B6041, Gosselies, Belgium.
authors.forename: Patricia
authors.initials: P
authors.lastname: Tebabi
authors.affiliation: Department of Clinical Chemistry, Hôpital Erasme, Université Libre de Bruxelles, 808, route de Lennik, B1070, Brussels, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brauner
authors.affiliation: Department of Hematology, Hôpital Erasme, Université Libre de Bruxelles, 808, route de Lennik, B1070, Brussels, Belgium.
authors.forename: Fleur Samantha
authors.initials: FS
authors.lastname: Benghiat
authors.affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 12, rue des Profs Jeener et Brachet, B6041, Gosselies, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Vanhollebeke
authors.affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 12, rue des Profs Jeener et Brachet, B6041, Gosselies, Belgium.|Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Liège, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Pays
mesh_terms: D000222:Adaptation, Physiological; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000633:toxicity*; D005786:Gene Expression Regulation; D006242:Haptoglobins / Q000032:analysis; D006801:Humans; D008075:Lipoproteins, HDL / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D012318:RNA Polymerase I / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D044967:Serum / Q000737:chemistry; D014158:Transcription, Genetic; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D014347:Trypanosoma brucei gambiense / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000502:physiology*
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D006242:Haptoglobins; D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C027079:hemoglobin-haptoglobin receptor; D012318:RNA Polymerase I