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Comment on "Not Lipoteichoic Acid but Lipoproteins Appear to Be the Dominant Immunobiologically Active Compounds in Staphylococcus aureus"

Biochemical Pharmacology, University of Konstanz, Konstanz, Germany

Recently, Hashimoto et al. (1) reported that lipoteichoic acid (LTA) extracted from a lipoprotein diacylglycerol transferase deletion (lgt) mutant of Staphylococcus aureus is immunologically inactive and concluded that the activity of LTA preparations generally lies in lipoprotein contaminants. These conclusions challenge our published (2, 3, 4, 5) and unpublished results.

Although referenced, the authors fail to mention that a fully synthetic complete LTA analog reflects the immunostimulatory activity of LTA of bacterial origin (3, 4). This activity cannot stem from lipoproteins.

Since neither the authors nor we see signs of lipoproteins in the nuclear magnetic resonance analysis of butanol-extracted, octylsepharose-purified LTA preparations (1, 2), they would need to prove that purified lipoproteins are at least 100-fold more potent than LTA to be considered relevant immunostimulatory structures. However, they have not been able to isolate or identify such structures.

We prepared LTA from the lgt mutant and respective wild-type bacteria by butanol extraction. Although we can confirm that LTA from the mutant does not stimulate the murine macrophage cell line J774A.1, the LTAs of both strains are equipotent in stimulating cytokine release in human whole blood (Fig. 1), arguably the more relevant system.

View larger version (14K): [in this window] [in a new window]   FIGURE 1. Similar activity of LTA from S. aureus DSM 20233, SA113 wild-type, and SA113 lgt mutant. Human whole blood, diluted 1/5 in RPMI 1640, was stimulated overnight with LTA prepared as described previously (2 ). TNF release was measured in the supernatants by ELISA, n = 12 blood donors. Data are given as mean ± SEM.

In conclusion, there remains strong evidence that LTAs are major immunostimulatory principles of Gram-positive bacteria. These data caution us from direct extrapolations from mice to humans.

References

1. Hashimoto, M., K. Tawaratsumida, H. Kariya, A. Kiyohara, Y. Suda, F. Krikae, T. Kirikae, F. Gotz. 2006. Not lipoteichoic acid but lipoproteins appear to be the dominant immunobiologically active compounds in Staphylococcus aureus. J. Immunol. 177: 3162-3169. [Abstract/Free Full Text]
2. Morath, S., A. Geyer, T. Hartung. 2001. Structure-function relationship of cytokine induction by lipoteichoic acid from Staphylococcus aureus. J. Exp. Med. 193: 393-397. [Abstract/Free Full Text]
3. Morath, S., A. Stadelmaier, A. Geyer, R. R. Schmidt, T. Hartung. 2002. Synthetic lipoteichoic acid from Staphylococcus aureus is a potent stimulus of cytokine release. J. Exp. Med. 195: 1635-1640. [Abstract/Free Full Text]
4. Deininger, S., A. Stadelmaier, S. von Aulock, S. Morath, R. R. Schmidt, T. Hartung. 2003. Definition of structural prerequisites for lipoteichoic acid-inducible cytokine induction by synthetic derivatives. J. Immunol. 170: 4134-4138. [Abstract/Free Full Text]
5. Morath, S., A. Geyer, I. Spreitzer, C. Hermann, T. Hartung. 2002. Structural decomposition and heterogeneity of commercial lipoteichoic acid preparations. Infect. Immun. 70: 938-944. [Abstract/Free Full Text]

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