The Journal of Experimental Medicine
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Published 17 June 2002. doi:10.1084/jem.20020322
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© Rockefeller University Press, 0022-1007/2002/6/1635/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 12, June 17, 2002 1635-1640

Brief Definitive Report

 Synthetic Lipoteichoic Acid from Staphylococcus aureus Is a Potent Stimulus of Cytokine Release

Siegfried Morath1, Andreas Stadelmaier2, Armin Geyer3, Richard R. Schmidt2 and Thomas Hartung1

1 Biochemical Pharmacology, University of Konstanz, 78457 Konstanz, Germany
2 Department of Chemistry, University of Konstanz, 78457 Konstanz, Germany
3 Institute for Organic Chemistry, University of Regensburg, 93040 Regensburg, Germany

Address correspondence to Thomas Hartung, Biochemical Pharmacology, University of Konstanz, 78457 Konstanz, Germany. Phone: 49-7531-884116; Fax: 49-7531-884117; E-mail: Thomas.Hartung{at}uni-konstanz.de

We recently purified lipoteichoic acid (LTA) from Staphylococcus aureus to more than 99% purity by a novel preparation method and deduced its structure with the first nuclear magnetic resonance (NMR) of a complete LTA. In contrast to Gram-negative lipopolysaccharides, this LTA requires the toll-like receptor (TLR)-2 and not TLR-4 for cytokine induction in monocytes and macrophages. To elucidate the structure–function relationships for LTA from S. aureus, the lipid anchor was prepared by either acidic hydrolysis of native LTA or chemical synthesis (gentiobiosyl-sn-dimyristoylglycerol). Next, a complete LTA molecule with six glycerophosphate units carrying four alanine plus one N-acetyl-glucosamine substituent was synthesized, which displayed the same potency to activate monocytes as native LTA. However, 100–1,000 times higher concentrations of the lipid anchor were required for cytokine induction. It is worthy to note that replacing D-alanine with L-alanine blunted the effect indicating stereoselective recognition. The structure identification of this synthesized and biologically active LTA was proven by NMR and matrix-assisted laser desorption-ionization mass spectrometry. We concluded that the lipid anchor, with its fatty acids, represents an integral part of the immunostimulatory activity of LTA, but requires additional structural components on the polyglycerophosphate backbone.

Key Words: tumor necrosis factor • Gram-positive bacteria • immunity, natural • structure–activity relationship • chemistry, organic


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