Distribution and kinetics of lipoprotein-bound lipoteichoic acid.
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Journal: 2003/June - Infection and Immunity
ISSN: 0019-9567
PUBMED: 12761109
Abstract:
Lipoteichoic acid (LTA), a major cell wall component of gram-positive bacteria, is an amphipathic anionic glycolipid with structural similarities to lipopolysaccharide (LPS) from gram-negative bacteria. LTA has been implicated as one of the primary immunostimulatory components that may trigger the systemic inflammatory response syndrome. Plasma lipoproteins have been shown to sequester LPS, which results in attenuation of the host response to infection, but little is known about the LTA binding characteristics of plasma lipid particles. In this study, we have examined the LTA binding capacities and association kinetics of the major lipoprotein classes under simulated physiological conditions in human whole blood (ex vivo) by using biologically active, fluorescently labeled LTA and high-performance gel permeation chromatography. The average distribution of an LTA preparation from Staphylococcus aureus in whole blood from 10 human volunteers revealed that >95% of the LTA was associated with total plasma lipoproteins in the following proportions: high-density lipoprotein (HDL), 68% +/- 10%; low-density lipoprotein (LDL), 28% +/- 8%; and very low density lipoprotein (VLDL), 4% +/- 5%. The saturation capacity of lipoproteins for LTA was in excess of 150 micro g/ml. The LTA distribution was temperature dependent, with an optimal binding between 22 and 37 degrees C. The binding of LTA by lipoproteins was essentially complete within 10 min and was followed by a subsequent redistribution from HDL and VLDL to LDL. We conclude that HDL has the highest binding capacity for LTA and propose that the loading and redistribution of LTA among plasma lipoproteins is a specific process that closely resembles that previously described for LPS (J. H. M. Levels, P. R. Abraham, A. van den Ende, and S. J. H. van Deventer, Infect. Immun. 68:2821-2828, 2001).
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Infect Immun 71(6): 3280-3284
PMID: 12761109

Distribution and Kinetics of Lipoprotein-Bound Lipoteichoic Acid

Departments of Vascular Medicine, Experimental Internal Medicine, Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands3
Corresponding author. Mailing address: Academic Medical Center, Department of Vascular Medicine, Room G1-114, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. Phone: 31-20-5665899. Fax: 31-20-5669232. E-mail: ln.avu.cma@slevel.h.
Received 2002 Nov 20; Revised 2003 Feb 4; Accepted 2003 Mar 10.
Copyright © 2003, American Society for Microbiology

Abstract

Lipoteichoic acid (LTA), a major cell wall component of gram-positive bacteria, is an amphipathic anionic glycolipid with structural similarities to lipopolysaccharide (LPS) from gram-negative bacteria. LTA has been implicated as one of the primary immunostimulatory components that may trigger the systemic inflammatory response syndrome. Plasma lipoproteins have been shown to sequester LPS, which results in attenuation of the host response to infection, but little is known about the LTA binding characteristics of plasma lipid particles. In this study, we have examined the LTA binding capacities and association kinetics of the major lipoprotein classes under simulated physiological conditions in human whole blood (ex vivo) by using biologically active, fluorescently labeled LTA and high-performance gel permeation chromatography. The average distribution of an LTA preparation from Staphylococcus aureus in whole blood from 10 human volunteers revealed that >95% of the LTA was associated with total plasma lipoproteins in the following proportions: high-density lipoprotein (HDL), 68% ± 10%; low-density lipoprotein (LDL), 28% ± 8%; and very low density lipoprotein (VLDL), 4% ± 5%. The saturation capacity of lipoproteins for LTA was in excess of 150 μg/ml. The LTA distribution was temperature dependent, with an optimal binding between 22 and 37°C. The binding of LTA by lipoproteins was essentially complete within 10 min and was followed by a subsequent redistribution from HDL and VLDL to LDL. We conclude that HDL has the highest binding capacity for LTA and propose that the loading and redistribution of LTA among plasma lipoproteins is a specific process that closely resembles that previously described for LPS (J. H. M. Levels, P. R. Abraham, A. van den Ende, and S. J. H. van Deventer, Infect. Immun. 68:2821-2828, 2001).

Abstract

Lipoteichoic acid (LTA), the major cell wall component of most gram-positive bacteria, is a member of a structurally related group of macroamphiphiles, the glycolipids, which consist of a hydrophobic diacylglycerol membrane anchor and a hydrophilic head group exposed on the outer bacterial surface (28). Experimental evidence has shown that LTA is a potent endotoxin capable during severe infection of inducing hemodynamic, hematological, and metabolic changes of a magnitude similar to those induced by lipopolysaccharide (LPS) from gram-negative bacteria (4). LTA preparations stimulate cells associated with cellular immunity to produce high levels of endogenous mediators of inflammation, such as tumor necrosis factor alpha (TNF-α) and the interleukins (IL-6, IL-1β, and IL-8), which are capable of sustaining an inflammatory state that may lead to septic shock and multiorgan failure (2, 4). Recognition of LPS by monocytes and macrophages is effected by the membrane-bound G-protein-linked receptor CD14 in a process which is accelerated by LPS binding protein (LBP) (14, 31). LBP acts together with soluble CD14 to monomerize LPS micelles and facilitate transport of the endotoxin to lipoproteins and macrophage receptors (29, 30). LBP and soluble CD14 have been found to bind LTA (22, 23) but with lower affinity than they bind LPS. In addition, Toll-like receptor proteins TLR-2 and TLR-4 of the macrophages have recently been implicated in endotoxin-induced intracellular signaling by LTA (9) and LPS (24, 25), respectively. In contrast to that of LPS, little is known about the mechanism of processing and clearing of LTA in the host.

Lipid metabolism appears to be extensively regulated during the host response to infection by increased levels of proinflammatory cytokines such as TNF-α, IL-1, and IL-6 or after cytokine administration in experimental animals and in humans (10). Disturbances in lipoprotein homeostasis appear to be characteristic of bacterial infection (1, 3, 11). The reduction in total cholesterol and in the apolipoprotein A-I and B contents of high-density lipoprotein (HDL) and low-density lipoprotein (LDL), respectively, coupled with an increase in very low density lipoprotein (VLDL) triglycerides, has been previously described (10). The magnitude of these alterations in lipoprotein composition appears to be related to the severity of the infection. Remarkably, all of these changes in the plasma lipid profiles were independent of the underlying diseases or the infectious agent responsible for initiating systemic inflammatory response syndrome. It has recently been proposed that disturbances in lipid metabolism may contribute to host defense, because the immune response is intimately linked to the metabolic response (12).

The expression of the scavenger receptor BI, an important mediator of cellular metabolism of HDL in the adrenal gland, also gives strong indications that the scavenger receptor BI may play a role in the processing of bacterial endotoxin during sepsis caused by gram-negative organisms (15). These changes in lipid metabolism also appear to form an integral part of the acute-phase response.

It has previously been shown that all lipoprotein classes are capable of binding LPS (26, 5, 21), which results in the attenuation of the host response to infection (6, 8, 19), and that lipoproteins are capable of inhibiting macrophage activation by isolated LTA preparations (13). The binding characteristics and kinetics of fluorescently labeled biologically active LPS with native plasma lipoproteins analyzed by high-performance gel chromatography (HPGC) have been recently described (16). To address the question of whether the interaction of LTA with lipoproteins is comparable to that of LPS, we examined the binding characteristics of plasma lipoproteins from healthy human subjects by using fluorescently labeled LTA and HPGC lipoprotein analysis. Here we report the LTA binding capacities of lipoproteins and the distribution and kinetics of lipoprotein-bound LTA under simulated physiological conditions in whole blood (ex vivo).

Notes

Editor: J. T. Barbieri

Notes
Editor: J. T. Barbieri

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