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Pedersen C.M.,University of Konstanz | Figueroa-Perez I.,University of Konstanz | Boruwa J.,University of Konstanz | Lindner B.,Leibniz Zentrum fur Medizin und Biowissenschaften | And 3 more authors.
Chemistry - A European Journal | Year: 2010

Streptococcus pneumoniae LTA is a highly complex glycophospholipid that consists of nine carbohydrate residues: three glucose, two galactosamine and two 2-acetamino-4-amino-2,4,6-trideoxygalactose (AATDgal) residues that are each differently linked, one ribitol and one diacylated glycerol (DAG) residue. Suitable building blocks for the glucose and the AATDgal residues were designed and their synthesis is described in this paper. These building blocks permitted the successful synthesis of the core structure Glcβ(1-3)AATDgalβ(1-3) Glcα(1-O)DAG in a suitably protected form for further chain extension (1b, 1c) and as unprotected glycolipid (1a) that was employed in biological studies. These studies revealed that 1a as well as 1 lead to interleukin-8 release, however not via TLR2 or TLR4 as receptor. The core: The synthesized core structure (1) of S. pneumoniae LTA (lipoteichoic acid) exhibited similar stimulation of interleukin-8 release as the recently synthesized complete LTA consisting of the core structure and the pseudopentasaccharidic repeating unit. Contrary to previous postulations, TLR2 is not the signalling receptor for these compounds. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pedersen C.M.,University of Konstanz | Figueroa-Perez I.,University of Konstanz | Lindner B.,Leibniz Zentrum fur Medizin und Biowissenschaften | Ulmer A.J.,Leibniz Zentrum fur Medizin und Biowissenschaften | And 2 more authors.
Angewandte Chemie - International Edition | Year: 2010

"Chemical Equation Preseted" Mixed signals: The glycophospholipid 1, consisting of two cholinylphosphoCalNAc units, two 2-acetamino-4-amino2,4,6- trideoxygalactose rings, three glucose residues each with different linkages to other sugar units, and a ribitolphosphate residue, has been synthesized. Target 1 is recognized by the immune system, but not by the TLR-2 signaling receptor as previously postulated. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Schmidt R.R.,University of Konstanz | Pedersen C.M.,Copenhagen University | Qiao Y.,University of Konstanz | Zahringer U.,Leibniz Zentrum fur Medizin und Biowissenschaften
Organic and Biomolecular Chemistry | Year: 2011

During infections caused by Gram-negative bacteria, lipopolysaccharide (LPS, endotoxin) has a dominant role leading to fulminant pro-inflammatory reactions in the host. As there is no LPS in Gram-positive bacteria, other microbial cell wall components have been identified to be the causative agent for the pro-inflammatory activity since also Gram-positive bacterial infections lead to comparable clinical symptoms and reactions. On search for the "Gram-positive endotoxin" a widely accepted hypothesis has been raised in that the lipoteichoic acids (LTAs) serve as pathogen-associated molecular patterns (PAMPs) during Gram-positive sepsis, although the amount necessary for a pro-inflammatory in vitro response is several orders of magnitude higher than that for LPS. Therefore, LTA cannot be considered to be "the (endo)toxin of Gram-positive bacteria". Although LPS and LTA show structural relatedness (amphiphilic, negatively charged glycophospholipids), they are structurally quite different from each other and one might expect that they are also recognized by different receptors of the innate immune system, the so called toll-like receptors 4 and 2 (TLR4 and TLR2), respectively. Based on their chemical structure, the LTAs were classified into four types (type I-IV) of which we have carefully investigated the LTA of Staphylococcus aureus (type I), Lactococcus garvieae (type II) and Streptococcus pneumoniae (type IV). Hence, these LTAs have been synthesized in our group and biologically evaluated with respect to their potency to activate cytokines in transiently TLR2/CD14-transfected human endothelial kidney cells (HEK 293) or human macrophages and whole blood cells. Although LTA of type I and IV are structurally quite different, especially in their hydrophilic moiety, they originally were believed to interact with the same receptor (TLR2). Hence, the chemical syntheses leading to structurally defined, non-contaminated stimuli have a major impact on the outcome and interpretation of these biological studies of the innate immune system. With this material, it became evident that synthetic LTA from S. aureus and S. pneumoniae are not recognized by TLR2. Instead, another receptor of the innate immune system, the lectin pathway of the complement, known since many years to interact with LTA in quite a specific way, has gained increasing attractivity. With the help of synthetic LTA we obtained first evidences that this receptor is indeed the pathogen recognition receptor (PRR) for LTA. © 2011 The Royal Society of Chemistry.

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