Journal Article

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

Truc, Philippe, Pays, Etienne, Vanhamme, Luc, Moestrup, Soren K, Vanhollebeke, Benoit, Nakajima, Kazunori, Nielsen, Marianne J, Watanabe, Yoshihisa

2007

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: alleles / Animals / Antibodies / Antigens, Neoplasm - blood / Antigens, Neoplasm - physiology / Apolipoprotein L1 / Apolipoproteins - blood / Apolipoproteins - physiology / Bacteria / Bacteriology / Biological Sciences / Blood / Blood cells / Blood Proteins - physiology / blood serum / Blotting, Western / Chromatography, Affinity / frameshift mutation / gene deletion / haptoglobins / Haptoglobins - physiology / HDL lipoproteins / high density lipoprotein / Humans / Immune System / Kinetics / Lipoproteins, HDL - blood / Lipoproteins, HDL - physiology / Lysosomes / Mice / Microscopes / Parasites / Proteins / Receptors / Recombinant Proteins - chemistry / Swelling / Toxins / Trypanocidal Agents - pharmacology / Trypanosoma brucei brucei / Trypanosoma brucei brucei - metabolism / Trypanosome / Trypanosomiasis, African - drug therapy