The role of lipoteichoic acids (LTAs) from Gram-positive bacteria as immunostimulatory molecules was controversial for many years, as inadequate preparation methods as well as heterogeneous and endotoxin-contaminated commercial preparations led to conflicting results. An improved purification methodology for LTA now yields potent bioactive and chemically defined material, which is currently being characterized in various models. A synthetic analogue of Staphylococcus aureus LTA has proven the structure/function relationship. The key role of D-alanine esters for the immune response of LTA was confirmed by synthetic derivatives. The glycolipid anchor of LTA plays a central role analogous to the lipid A of LPS. Methodological aspects and criteria for quality assessment of LTA preparations are discussed.
Bone RCGram-positive organisms and sepsis. Arch Intern Med1994; 154: 26—34.
3.
Opal SM, Cohen J.Clinical Gram-positive sepsis: does it fundamentally differ from Gram-negative bacterial sepsis?Crit Care Med1999; 27: 1608—1616.
4.
Williams DH, Bardsley B.Die Vancomycin-Antibiotica und der Kampf gegen resistente Bakterien. Angew Chem1999; 111: 1264—1286.
5.
Harris TN, Harris S.Agglutination by human sera of erythrocytes incubated with streptococcal culture concentrates. J Bacteriol1953; 66: 159—165.
6.
Pakula R., Walczak W.An erythrocyte-sensitising factor common to staphylococci and haemolytic streptococci . Acta Microbiol Pol1955; 4: 235—243.
7.
Jackson RW, Moskowitz M.Nature of a red cell sensitizing substance from streptococci. J Bacteriol1966; 91: 2205—2209.
8.
Dishon T., Finkel R., Marcus Z., Ginsburg I.Cell-sensitizing products of streptococci. Immunology1967; 13: 555—564.
9.
Wicken AJ, Knox KWLipoteichoic acids: a new class of bacterial antigen. Science1975; 187: 1161—1167.
10.
Hewett MJ, Knox KW, Wicken AJStudies on the group F antigen of lactobacilli: detection of antibodies by haemagglutination. J Gen Microbiol1970; 60: 315—322.
11.
Leopold K., Fischer W.Hydrophobic interaction chromatography fractionates lipoteichoic acid according to the size of the hydrophilic chain: a comparative study with anion-exchange and affinity chromatography for suitability in species analysis. Anal Biochem1992; 201: 350—355.
12.
Fischer W.Lipoteichoic acids and lipoglycans. In: Ghuysen J-M, Hakenbeck R. (eds) Bacterial Cell Wall. Amsterdam: Elsevier Science, 1994; 199—215.
13.
Keller R., Fischer W., Keist R., Bassetti S.Macrophage response to bacteria: induction of marked secretory and cellular activities by lipoteichoic acids. Infect Immun1992; 60: 3664—3672.
14.
Kusunoki T. , Hailman E., Juan TS, Lichenstein HS, Wright SDMolecules from Staphylococcus aureus that bind CD14 and stimulate innate immune responses. J Exp Med1995; 182: 1673—1682.
15.
Kusunoki T. , Wright SDChemical characteristics of Staphylococcus aureus molecules that have CD14-dependent cell-stimulating activity. J Immunol1996; 157: 5112—5117.
16.
Morath S., Geyer A., Hartung T.Structure—function relationship of cytokine induction by lipoteichoic acid from Staphylococcus aureus. J Exp Med2001; 193: 393—397.
17.
Morrison DC , Leive L.: Fractions of lipopolysaccharide from Escherichia coli O111:B4 prepared by two extraction procedures. J Biol Chem1975; 250: 2911—2919.
18.
Okamoto M., Kaji R., Kasetani H. et al. Purification and characterization of interferon-gamma-inducing molecule of OK-432, a penicillin-killed streptococcal preparation, by monoclonal antibody neutralizing interferon-gamma-inducing activity of OK-432. J Immunother1993; 13: 232—242.
19.
Fischer W., Koch HU, Haas R.Improved preparation of lipoteichoic acids. Eur J Biochem1983; 133: 523—530.
20.
Morath S., Geyer A., Spreitzer I., Hermann C., Hartung T.Structural decomposition and heterogeneity of commercial lipoteichoic acid preparations. Infect Immun2002; 70: 938—944.
21.
Hermann C., Spreitzer I., Schroder NW et al. Cytokine induction by purified lipoteichoic acids from various bacterial species — role of LBP, sCD14, CD14 and failure to induce IL-12 and subsequent IFNgamma release. Eur J Immunol2002; 32: 541—551.
22.
Stadelmaier A., Morath S., Hartung T., Schmidt RRSynthesis of the first fully active lipoteichoic acid. Angew Chem Int Edn Engl2003; 42: 916—920.
23.
Morath S., Stadelmaier A., Geyer A., Schmidt RR, Hartung T.Synthetic lipoteichoic acid from Staphylococcus aureus is a potent stimulus of cytokine release. J Exp Med2002; 195: 1635—1640.
24.
Lehner MD, Morath S., Michelsen KS, Schumann RR, Hartung T.Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different Toll-like receptors independent of paracrine mediators . J Immunol2001; 166: 5161—5167.
25.
Deininger S., Stadelmaier A., von Aulock S. et al. Definition of structural prerequisites for lipoteichoic acid-inducible cytokine induction by synthetic derivatives. J Immunol2003; 170: 4134—4138.
26.
Ellingsen E. , Morath S., Flo T. et al. Induction of cytokine production in human T cells and monocytes by highly purified lipoteichoic acid: involvement of Toll-like receptors and CD14. Med Sci Monit2002; 8: BR149—BR156.
27.
Schroder NW , Morath S., Alexander C. et al. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J Biol Chem2003; 278: 15587—15594.
28.
Hoebe K., Georgel P., Rutschmann S. et al. CD36 is a sensor of diacylglycerides. Nature2005; 433: 523—527.
29.
von Aulock S., Morath S., Hareng L. et al. Lipoteichoic acid from Staphylococcus aureus is a potent stimulus for neutrophil recruitment. Immunobiology2003; 208: 413—422.
30.
Mattsson E. , Hartung T., Morath S., Egesten A.Highly purified lipoteichoic acid from Staphylococcus aureus induces procoagulant activity and tissue factor expression in human monocytes but is a weak inducer in whole blood: comparison with peptidoglycan . Infect Immun2004; 72: 4322—4326.
31.
Lynch NJ, Roscher S., Hartung T. et al. L-Ficolin specifically binds to lipoteichoic acid, a cell wall constituent of Gram-positive bacteria, and activates the lectin pathway of complement. J Immunol2004; 172: 1198—1202.
32.
Hirschfeld M., Ma Y., Weis JH, Vogel SN, Weis JJRepurification of lipopolysaccharide eliminates signaling through both human and murine Toll-like receptor 2. J Immunol2000; 165: 618—622.
33.
Huff E.Lipoteichoic acid, a major amphiphile of Gram-positive bacteria that is not readily extractable. J Bacteriol1982; 149: 399—402.
34.
Fischer W., Koch HUAlanine ester substitution and its effect on the biological properties of lipoteichoic acids. In: Wicken GDSaAJ. (ed) Chemistry and Biological Activities of Bacterial Surface Amphiphiles . New York: Academic Press, 1981; 181—194.
35.
Jaber BL, Barrett TW, Cendoroglo Neto M. et al. Removal of cytokine inducing substances by polymyxin-B immobilized polystyrene-derivative fibers during in vitro hemoperfusion of 10% human plasma containing Staphylococcus aureus challenge. Asaio J1998; 44: 48—53.
36.
Wicken AJ, Broady KW, Ayres A., Knox KWProduction of lipoteichoic acid by lactobacilli and streptococci grown in different environments. Infect Immun1982; 36: 864—869.
37.
Hardy L., Jacques NA, Forester H. et al. Effect of fructose and other carbohydrates on the surface properties, lipoteichoic acid production, and extracellular proteins of Streptococcus mutans Ingbritt grown in continuous culture. Infect Immun1981; 31: 78—87.
38.
Fischer W., Rosel P.The alanine ester substitution of lipoteichoic acid (LTA) in Staphylococcus aureus. FEBS Lett1980; 119: 224—226.
39.
Koch HU, Doker R., Fischer W.Maintenance of D-alanine ester substitution of lipoteichoic acid by reesterification in Staphylococcus aureus. J Bacteriol1985 ; 164: 1211—1217.
40.
MacArthur AE , Archibald AREffect of culture pH on the D-alanine ester content of lipoteichoic acid in Staphylococcus aureus. J Bacteriol1984; 160: 792—793.
41.
Wicken AJ, Gibbens JW, Knox KWComparative studies on the isolation of membrane lipoteichoic acid from Lactobacillus fermenti. J Bacteriol1973; 113: 365—372.
42.
Fischer W.Lipoteichoic acid and lipids in the membrane of Staphylococcus aureus. Med Microbiol Immunol (Berl) 1994; 183: 61—76.
43.
Galanos C., Luderitz O., Westphal O.Preparation and properties of a standardized lipopolysaccharide from Salmonella abortus equi (Novo-Pyrexal). Zentralbl Bakteriol [Orig A] 1979; 243: 226—244.
Fischer W.One-step purification of bacterial lipid macroamphiphiles by hydrophobic interaction chromatography. Anal Biochem1991; 194: 353—358.
46.
Silvestri LJ , Craig RA, Ingram LO, Hoffmann EM, Bleiweis ASPurification of lipoteichoic acids by using phosphatidyl choline vesicles. Infect Immun1978; 22: 107—118.
47.
Muhlradt PF , Kiess M., Meyer H., Sussmuth R., Jung G.Isolation, structure elucidation, and synthesis of a macrophage stimulatory lipopeptide from Mycoplasma fermentans acting at picomolar concentration. J Exp Med1997 ; 185: 1951—1958.
48.
Fischer W., Koch HU, Rosel P., Fiedler F.Alanine ester-containing native lipoteichoic acids do not act as lipoteichoic acid carrier. Isolation, structural and functional characterization. J Biol Chem1980; 255: 4557—4562.
