title: Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum.
abstract: Apolipoprotein L-I (apoL-I) is a human high-density lipoprotein (HDL) component able to kill Trypanosoma brucei brucei by forming anion-selective pores in the lysosomal membrane of the parasite. Another HDL component, haptoglobin-related protein (Hpr), has been suggested as an additional toxin required for full trypanolytic activity of normal human serum. We recently reported the case of a human lacking apoL-I (apoL-I(-/-)HS) as the result of frameshift mutations in both apoL-I alleles. Here, we show that this serum, devoid of any trypanolytic activity, exhibits normal concentrations of HDL-bound Hpr. Conversely, the serum of individuals with normal HDL-bound apoL-I but who lack Hpr and haptoglobin [Hp(r)(-/-)HS] as the result of gene deletion (anhaptoglobinemia) exhibited phenotypically normal but delayed trypanolytic activity. The trypanolytic properties of Hp(r)(-/-)HS were mimicked by free recombinant apoL-I, whereas recombinant Hpr did not affect trypanosomes. The lysis delay observed with either Hp(r)(-/-)HS or recombinant apoL-I could entirely be attributed to a defect in the uptake of the lytic components. Thus, apoL-I is responsible for the trypanolytic activity of normal human serum, whereas Hpr allows fast uptake of the carrier HDL particles, presumably through their binding to an Hp/Hpr surface receptor of the parasite.
authors.affiliation: Laboratory of Molecular Parasitology, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 12 Rue des Profs Jeener et Brachet, B6041 Gosselies, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Vanhollebeke
authors.forename: Marianne J
authors.initials: MJ
authors.lastname: Nielsen
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Philippe
authors.initials: P
authors.lastname: Truc
authors.forename: Luc
authors.initials: L
authors.lastname: Vanhamme
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakajima
authors.forename: Soren K
authors.initials: SK
authors.lastname: Moestrup
authors.forename: Etienne
authors.initials: E
authors.lastname: Pays
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000097:blood / Q000502:physiology*; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000097:blood / Q000502:physiology*; D001798:Blood Proteins / Q000502:physiology*; D015153:Blotting, Western; D002846:Chromatography, Affinity; D006242:Haptoglobins / Q000502:physiology*; D006801:Humans; D007107:Immune System; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood / Q000502:physiology*; D051379:Mice; D011994:Recombinant Proteins / Q000737:chemistry; D014344:Trypanocidal Agents / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: C108666:APOL1 protein, human; D000951:Antigens, Neoplasm; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D001798:Blood Proteins; C058632:HPR protein, human; D006242:Haptoglobins; D008075:Lipoproteins, HDL; D011994:Recombinant Proteins; D014344:Trypanocidal Agents