Human High Density Lipoproteins Are Platforms for the Assembly of Multi-component Innate Immune Complexes

April M Shiflett,Joseph R Bishop,Amit Pahwa,Stephen L Hajduk

doi:10.1074/jbc.m503510200

Abstract

Human innate immunity to non-pathogenic species of African trypanosomes is provided by human high density lipoprotein (HDL) particles. Here we show that native human HDLs containing haptoglobin-related protein (Hpr), apolipoprotein L-I (apoL-I) and apolipoprotein A-I (apoA-I) are the principle antimicrobial molecules providing protection from trypanosome infection. Other HDL subclasses containing either apoA-I and apoL-I or apoA-I and Hpr have reduced trypanolytic activity, whereas HDL subclasses lacking apoL-I and Hpr are non-toxic to trypanosomes. Highly purified, lipid-free Hpr and apoL-I were both toxic to Trypanosoma brucei brucei but with specific activities at least 500-fold less than those of native HDLs, suggesting that association of these apolipoproteins within the HDL particle was necessary for optimal cytotoxicity. These studies show that HDLs can serve as platforms for the assembly of multiple synergistic proteins and that these assemblies may play a critical role in the evolution of primate-specific innate immunity to trypanosome infection.

Highlights

One such innate immune activity in the serum of humans, apes, and old world monkeys limits the host range of Trypanosoma brucei brucei to non-primate mammals [1]
In the studies reported here we show that haptoglobin-related protein (Hpr) and apolipoprotein L-I (apoL-I) assemble into the same native human high density lipoprotein (HDL) particle, that purified apoL-I and Hpr are both T. b. brucei-specific toxins, and that assembly of these proteins into the same HDL particle resulted in a synergistic increase in trypanolytic activity
We have presented evidence that a minor subclass of HDL containing Hpr was trypanolytic, whereas others have shown that apoL-I is toxic to T. b. brucei [12, 13]

Summary

Introduction

One such innate immune activity in the serum of humans, apes, and old world monkeys limits the host range of Trypanosoma brucei brucei to non-primate mammals [1] This activity fractionates with a minor subclass of human HDL termed trypanosome lytic factor 1 (TLF-1) that, like all HDLs, is composed of apolipoproteins, phospholipids, and neutral lipids [2, 3]. When chimp sera were tested for the presence of Hpr none was detectable, indicating that chimps retain the Hpr gene they lack Hpr in their serum [19] Another primate-specific protein, apoL-I, has recently been shown to possess cytotoxic activity against T. b. Brucei-resistant primates such as the baboon and the sooty mangabey do not contain apoL-I in their serum, Hpr. HDLs Are Platforms for Multiple Synergistic Protein Assembly is present [19, 24]. Our results suggest that HDL assembly and remodeling play important roles in the formation of multi-component assemblages in the circulation that may accentuate innate immune protection against infectious agents

Methods

Results

Conclusion