Abstract
Trypanosome lytic factor (TLF) is a high-density lipoprotein (HDL) subclass providing innate protection to humans against infection by the protozoan parasite Trypanosoma brucei brucei. Two primate-specific plasma proteins, haptoglobin-related protein (Hpr) and apolipoprotein L-1 (ApoL-1), have been proposed to kill T. b. brucei both singularly or when co-assembled into the same HDL. To better understand the mechanism of T. b. brucei killing by TLF, the protein composition of TLF was investigated using a gentle immunoaffinity purification technique that avoids the loss of weakly associated proteins. HDL particles recovered by immunoaffinity absorption, with either anti-Hpr or anti-ApoL-1, were identical in protein composition and specific activity for T. b. brucei killing. Here, we show that TLF-bound Hpr strongly binds Hb and that addition of Hb stimulates TLF killing of T. b. brucei by increasing the affinity of TLF for its receptor, and by inducing Fenton chemistry within the trypanosome lysosome. These findings suggest that TLF in uninfected humans may be inactive against T. b. brucei prior to initiation of infection. We propose that infection of humans by T. b. brucei causes hemolysis that triggers the activation of TLF by the formation of Hpr–Hb complexes, leading to enhanced binding, trypanolytic activity, and clearance of parasites.
Highlights
African trypanosomes are blood parasites of mammals in sub-Saharan Africa that cause chronic wasting diseases in both humans and domestic animals [1]
We show that haptoglobin-related protein (Hpr) contributes to trypanosome lytic factor (TLF) toxicity to trypanosomes because it binds hemoglobin (Hb)
We postulate that trypanosome infection causes increased vascular levels of Hb, resulting in the formation of TLF–Hb complexes that may be important in ‘‘arming’’ the human innate immune system to clear the circulation of certain African trypanosomes
Summary
African trypanosomes are blood parasites of mammals in sub-Saharan Africa that cause chronic wasting diseases in both humans and domestic animals [1]. The three subspecies of Trypanosoma brucei are defined by their host range, geographical distribution, and course of disease [1,2,3]. Brucei does not cause human disease because of its susceptibility to an innate immune activity in human serum. This protection is conferred by trypanosome lytic factor (TLF), a minor subclass of human high-density lipoprotein (HDL) [5,6,7]
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