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Ken M. Kengatharan^*, Sjef De Kimpe, Caroline Robson^*, Simon J. Foster, and Christoph Thiemermann^*

From the ^* William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom; the Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Science, Utrecht University, 3584 CA Utrecht, The Netherlands; and the Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, United Kingdom

The incidence of septic shock caused by gram-positive bacteria has risen markedly in the last few years. It is largely unclear how gram-positive bacteria (which do not contain endotoxin) cause shock and multiple organ failure. We have discovered recently that two cell wall fragments of the pathogenic gram-positive bacterium Staphylococcus aureus, lipoteichoic acid (LTA) and peptidoglycan (PepG), synergize to cause the induction of nitric oxide (NO) formation, shock, and organ injury in the rat. We report here that a specific fragment of PepG, N-acetylglucosamine-β-[1 4]-N-acetylmuramyl-L-alanine–D-isoglutamine, is the moiety within the PepG polymer responsible for the synergism with LTA (or the cytokine interferon ) to induce NO formation in the murine macrophage cell line J774.2. However, this moiety is also present in the PepG of the nonpathogenic bacterium Bacillus subtilis. We have discovered subsequently that S. aureus LTA synergizes with PepG from either bacterium to cause enhanced NO formation, shock, and organ injury in the rat, whereas the LTA from B. subtilis does not synergize with PepG of either bacterium. Thus, we propose that the structure of LTA determines the ability of a particular bacterium to cause shock and multiple organ failure (pathogenicity), while PepG acts to amplify any response induced by LTA.

Key Words: gram-positive shock • nitric oxide • peptidoglycan • lipoteichoic acid

C. Thiemermann is a Senior Fellow of the British Heart Foundation (FS 016/96). S.J. Foster is supported by the Royal Society. This work was supported by a Biomed II grant of the European Commission.

Abbreviations used: AE-ITU, aminoethyl-isothiourea; ALT, alanine aminotransferase; D- or L-ala, D- or L-alanine; iNOS, inducible NOS; L-lys, L-lysine; L-NMMA, N^G-methyl-L-arginine; LTA, lipoteichoic acid; MTT, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAG, N-acetylglucosamine; NAM, N-acetylmuramic acid; NAG-NAM-L-ala- D-isoglutamine, N-acetylglucosamine-β-[1 4]-N-acetylmuramyl-L-alanine- D-isoglutamine; NO, nitric oxide; NOS, NO synthase; PepG, peptidoglycan; RASMC, rat aortic smooth muscle cell(s); SALE, Staphylococcus aureus lytic enzyme.

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