Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum

doi:10.1073/pnas.0609902104

Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum

*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;
^†Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus, Denmark;
^‡Japanese Red Cross Central Blood Institute, Tokyo 135-8521, Japan;
^§Institut de Recherche pour le Développement, Unité de Recherche 117 Trypanosomoses Africaines, Instituto de Combate e Controlo das Tripanosossomiases, CP 2657 Luanda, Angola; and
^¶Tokyo Red Cross Blood Center, Tokyo 135-8639, Japan

Edited by P. Borst, The Netherlands Cancer Institute, Amsterdam, The Netherlands, and approved January 19, 2007 (received for review November 8, 2006)

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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: epays{at}ulb.ac.be
Author contributions: B.V. and E.P. designed research; B.V. performed research; M.J.N., Y.W., P.T., L.V., K.N., and S.K.M. contributed new reagents/analytic tools; B.V. and E.P. analyzed data; and B.V. and E.P. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Abbreviations:

TLF,

trypanosome lytic factor;

FCS,

fetal calf serum;

NHS,

normal human serum;

HDL,

high-density lipoproteins;

apoL-I,

apolipoprotein L-I;

Hpr,

haptoglobin-related protein;

Hp,

haptoglobin;

apoA-I,

apolipoprotein A-I;

Hp(r)−/−HS,

human serum devoid of Hp and Hpr;

apoL-I−/−HS,

human serum devoid of apoL-I.