Cytokine induction by Gram-positive bacteria

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Gram-positive and Gram-negative bacteria induce inflammatory reactions which are clinically similar. While structure/ function relationships for Gram-negative endotoxins (lipopoly- saccharides, LPS) are established, for the equally important Gram-positive pathogens such studies are lacking. We have recently isolated the lipoteichoic acid (LTA) from Staphylo- coccus aureus, analyzed the structure and shown that LTA is the an immune activator operating via the tlr-2 receptor. LTA however, induces a more narrow spectrum of inflammatory reactions than LPS. To explain the lower animal toxicity of LTA, we attributed this to a lack of IL-12 and subsequent IFNg induction. Indeed, LTA became toxic in mice when IFNg was substituted. Work program is: The cytokine release from blood by tlr-2 agonists such as LTA (various species), candida mannans, Borrelia antigens, lipoarabinomannan and MALP-2, will be compared to check whether the lack of IL-12 induction represents a general characteristics of tlr-2 agonists. The response of primary mouse macrophages shall be compared to human monocytes. Then, the IL-12 promoter motifs for transcriptional activators will be searched for putative differences between LPS and LTA signaling. Based on previous work, the independent or synergistic induction of IFNg by muropeptides, commercial superantigens and bacterial DNA will be tested. Purification and identification by fractionation/solvent extraction/chroma- tography of this bioactivity is primary goal. The identified synergistic component will be given to mice together with LTA in order to establish a Gram-positive animal model analogous to LPS shock or galactosamine/LPS liver injury. The basic characteristics of such an animal model (dose-dependence, cytokine pattern, histopathology) will be studied.