Characterization of the Human Serum Trypanosome Toxin, Haptoglobin-related Protein

Muranjan, Madhavi; Nussenzweig, Victor; Tomlinson, Stephen

doi:10.1074/jbc.273.7.3884

Cited by 50 publications

(45 citation statements)

References 23 publications

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“…The present study has examined the process by which ROS kills the unicellular pathogen T. b. brucei. ROS production might be an important negative regulator of the trypanosome infection cycle, as evidenced by the role of ROS in innate resistance to trypanosome infections of humans [4][5][6][7] and livestock [10][11][12] [43,44]. In the present study we show that Ca# + stabilization protects T. b. brucei from the deleterious effects of ROS.…”

Section: Discussionsupporting

confidence: 52%

“…Innate resistance to trypanosome infections occurs in some species owing to nonimmune-mediated mechanisms of parasite killing. Human resistance to Trypanosoma brucei brucei could result from the production of reactive oxygen species (ROS) within the trypanosome after transport of the human haptoglobin-related protein to the lysosome [4][5][6][7]. T. brucei rhodesiense resists lysis and is infectious to humans [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Reactive oxygen species activate a Ca2+-dependent cell death pathway in the unicellular organism Trypanosoma brucei brucei

Ridgley

Xiong²,

Ruben³

1999

Biochemical Journal

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Here we examine a cell death process induced by reactive oxygen species (ROS) in the haemoflagellate Trypanosoma brucei brucei. Ca# + distribution in cellular compartments was measured with stable transformants expressing aequorin targeted to the cytosol, nucleus or mitochondrion. Within 1.5 h of ROS production, mitochondrial Ca# + transport was impaired and the Ca# + barrier between the nuclear envelope and cytosol was disrupted. Consequently the mitochondrion did not accumulate Ca# + efficiently in response to an extracellular stimulus, and excess Ca# + accumulated in the nucleus. The terminal transferase deoxytidyl uridine end labelling assay revealed that, 5 h after treatment with ROS, extensive fragmentation of nuclear DNA occurred in over 90 % of the cells. Permeability changes in the plasma membrane did not occur until an additional 2 h had elapsed. The intracellular

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species activate a Ca2+-dependent cell death pathway in the unicellular organism Trypanosoma brucei brucei

Ridgley

Xiong²,

Ruben³

1999

Biochemical Journal

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“…34 Accordingly, the Hpr levels (ϳ 30-40 mg/L) are more than 10-fold lower than the Hp levels. 35,36 Unlike Hp, the Hpr serum concentration seems rather resistant to intravascular hemolysis. 35,36 The majority of Hpr is associated with 2 serum complexes referred to as trypanosome lytic factors 1 (TLF1) and 2 (TLF2), which both are able to induce lysis of Trypanosoma brucei brucei (T b brucei), an African protozoan parasite that is transmitted to the mammalian bloodstream through the bite of infected tsetse flies and is the causative agent of the lethal disease sleeping sickness in cattle and other animals.…”

Section: Expression and Presence In Plasmamentioning

confidence: 99%

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Nielsen

Moestrup

2009

Blood

138

109

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Haptoglobin, the haptoglobin-hemoglobin receptor CD163, and the heme oxygenase-1 are proteins with a well-established function in the clearance and metabolism of "free" hemoglobin released during intravascular hemolysis. This scavenging system counteracts the potentially harmful oxidative and NO-scavenging effects associated with "free" hemoglobin, and, furthermore, elicits an anti-inflammatory response. In the late primate evolution, haptoglobin variants with distinct functions have arisen, including haptoglobin polymers and the haptoglobin-related protein. The latter associates with a subspecies of high-density lipoprotein (HDL) particles playing a crucial role in the innate immunity against certain trypanosome parasites. Recent studies have elucidated this fairly sophisticated immune defense mechanism that takes advantage of a trypanosomal haptoglobin-hemoglobin receptor evolved to supply the parasite with heme. Because of the high resemblance between haptoglobin and haptoglobinrelated protein, the receptor also takes up the complex of hemoglobin and the HDL- IntroductionHaptoglobin (Hp), an abundant acute phase plasma glycoprotein of the ␣ 2 -globulin fraction, was initially reported in 1938 by Polonovski and Jayle to be a "plasma substance" that binds hemoglobin (Hb). 1 In agreement with this initial characterization and its designation as "haptoglobin" (Greek: haptein, "to bind" ϩ [hemo]globin), Hp has a well-established role in binding of "free" Hb released into the circulation during the process of intravascular hemolysis. By capturing the liberated Hb, Hp protects against toxic effects associated with Hb, and it facilitates Hb clearance through endocytosis by the macrophage scavenger receptor CD163. 2 Later studies of human and primate plasma revealed variant forms of Hp as well as the existence of an Hp-related protein (Hpr) that recently has been shown also to bind Hb. As highlighted in this review, novel functions of Hp depend on high-affinity interactions with Hb and lipoprotein and subsequent receptor recognition of the resulting complexes. Toxicity of hemoglobin released during intracellular hemolysisIntravascular hemolysis, which accounts for approximately 10% to 20% of total red blood cell destruction, 3 changes Hb from being an intracellular O 2 /CO 2 transporter to a highly toxic substance in plasma. This toxicity arises from the heme iron, which can react with endogenous hydrogen peroxide to produce free radicals, which in turn may cause severe oxidative tissue damage, 4 particularly in the kidney. 5 In addition to the oxidative toxicity of Hb, Hb is a potent scavenger of nitric oxide (NO), a signaling molecule that functions as a critical regulator of smooth muscle relaxation, endothelial adhesion molecule expression, and platelet activation and aggregation. 6,7 The reaction of Hb with NO is fast and irreversible, leading to the production of nitrate and methemoglobin. If allowed to occur, this Hbmediated consumption of vascular NO, referred to as NOscavenging, thus limits the bioavailabili...

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“…However, Hpr does not bind hemoglobin, and its physiological function is unknown (9,16). The role of Hpr in T. b. brucei killing was initially proposed based on its fractionation with TLF-1 and its presence in lipid-deficient human serum fractions that also contain trypanosome killing activity (TLF-2) (12,17,18).…”

mentioning

confidence: 99%

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

Shiflett

Bishop

Pahwa

et al. 2005

Journal of Biological Chemistry

146

145

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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. High density lipoprotein (HDL)2 has several well established physiological activities. The best understood of these is the ability of HDL to protect against atherosclerotic cardiovascular disease by promoting the efflux of excess cholesterol from peripheral tissues and its subsequent transport to the liver for excretion. In addition, apolipoproteins and enzymes carried by HDL have antioxidant activities that inhibit the oxidative modification of low density lipoprotein (LDL), thereby reducing the atherogenicity of these lipoproteins. A less well known activity of HDL is an antimicrobial property that protects some primates from infection by certain eukaryotic pathogens. In these primate species, HDL apolipoproteins have been proposed to have novel innate immune protective functions that provide selective protection against infection.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). Trypanosome killing by these cytotoxic HDLs requires high affinity binding to receptors on the trypanosome surface, endocytosis, and lysosomal localization (4 -8). Following lysosomal acidification, destabilization of the lysosome membrane is facilitated by either free radical-mediated lipid peroxidation or pore formation (9 -11). Two HDL-associated proteins have been implicated in the toxicity of TLF-1, haptoglobin-related protein (Hpr) and apolipoprotein L-I (apoL-I) (12, 13).Haptoglobin-related protein differs by only 27 amino acids from human haptoglobin, an acute phase serum protein that binds hemoglobin released from red blood cells during trauma or infection and transfers the hemoglobin to liver cells for detoxification (14,15). However, Hpr does not bind hemoglobin, and...

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Characterization of the Human Serum Trypanosome Toxin, Haptoglobin-related Protein

Cited by 50 publications

References 23 publications

Reactive oxygen species activate a Ca2+-dependent cell death pathway in the unicellular organism Trypanosoma brucei brucei

Reactive oxygen species activate a Ca2+-dependent cell death pathway in the unicellular organism Trypanosoma brucei brucei

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

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

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