Biopolym. Cell. 2008; 24(1):3-13.
Peptidoglycan Staphylococcus aureus and its immune-biological features
1Pozur V. V., 1Skivka L. M., 2Potebnia G. P.
  1. Taras Shevchenko National University of Kyiv
    64, Volodymyrska Str., Kyiv, Ukraine, 01601
  2. R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine
    45, Vasilkivska Str., Kyiv, Ukraine, 01022


Bacterial subcellular components and metabolites are potent biologically active substances with inherent immunomodulating and adjuvant properties. Peptidoglycan (murein) is the major, unique, and essential component of the cell wall of virtually all bacteria. Murein and its muropeptide derivatives are considered to be potential virulence factors. Peptidoglycans of different bacteria have distinguishing features, but all of them are not present in eukaryotes, and, therefore, they are excellent targets for innate immune system. In this review the data on structural specificities of S. aureus peptidoglycan and its effect on immune system are summarized.
Keywords: peptidoglycan, cell walls, muropeptide, immunomodulation, adjuvant action


[1] Cabeen MT, Jacobs-Wagner C. Bacterial cell shape. Nat Rev Microbiol. 2005;3(8):601-10.
[2] Beveridge TJ, Pouwels PH, Sara M, Kotiranta A, Lounatmaa K, Kari K, Kerosuo E, Haapasalo M, Egelseer EM, Schocher I, Sleytr UB, Morelli L, Callegari ML, Nomellini JF, Bingle WH, Smit J, Leibovitz E, Lemaire M, Miras I, Salamitou S, Beguin P, Ohayon H, Gounon P, Matuschek M, Koval SF. Functions of S-layers. FEMS Microbiol Rev. 1997;20(1-2):99-149.
[3] Boneca IG. The role of peptidoglycan in pathogenesis. Curr Opin Microbiol. 2005;8(1):46-53.
[4] Pozur VK. immunological activity of bacterial peptidoglycan. K.: Fitosotsiotsentr, 2002. 236 p.
[5] van Heijenoort J. Formation of the glycan chains in the synthesis of bacterial peptidoglycan. Glycobiology. 2001;11(3):25R-36R.
[6] Rosenthal RS, Dziarski R. Isolation of peptidoglycan and soluble peptidoglycan fragments. Methods Enzymol. 1994;235:253-85.
[7] Dziarski R, Gupta D. Staphylococcus aureus peptidoglycan is a toll-like receptor 2 activator: a reevaluation. Infect Immun. 2005;73(8):5212-6.
[8] Moreillon P, Majcherczyk PA. Proinflammatory activity of cell-wall constituents from gram-positive bacteria. Scand J Infect Dis. 2003;35(9):632-41.
[9] Goran SE, Navashin SM. Preparation of immunologically active fragments of peptidoglycan of bacterial cell wall. Immunomodulators. M., 1987:77–89.
[10] Franklin T. J. Snowe Biochemistry of antimicrobial action. Translated from English. M. Mir, 1984. 240.
[11] Schleifer KH, Kandler O. Peptidoglycan types of bacterial cell walls and their taxonomic implications. Bacteriol Rev. 1972;36(4):407-77.
[12] Barzilai A, Hyatt AC, Hodes DS. Demonstration of differences between strains of Staphylococcus aureus by peptidoglycan fingerprinting. J Infect Dis. 1984;150(4):583-8.
[13] Tosi MF. Innate immune responses to infection. J Allergy Clin Immunol. 2005;116(2):241-9; quiz 250.
[14] Uehara A, Fujimoto Y, Kawasaki A, Kusumoto S, Fukase K, Takada H. Meso-diaminopimelic acid and meso-lanthionine, amino acids specific to bacterial peptidoglycans, activate human epithelial cells through NOD1. J Immunol. 2006;177(3):1796-804.
[15] Traub S, von Aulock S, Hartung T, Hermann C. MDP and other muropeptides--direct and synergistic effects on the immune system. J Endotoxin Res. 2006;12(2):69-85.
[16] Kaliuzhin OV. Muramyl dipeptide derivatives in experimental and clinical use. Zh Mikrobiol Epidemiol Immunobiol. 1998;(1):104-8.
[17] Sepiashvili RI. Immunotropic drugs: classification, problems and prospects. Allergology and immunology. 2001; 2(1):39–45.
[18] Masek K. Immunopharmacology of muramyl peptides. Fed Proc. 1986;45(11):2549-51.
[19] Farghali H, Buchar E, Machkov? Z, Kamen?kov? L, Masek K. Muramyl dipeptide and carbon tetrachloride hepatotoxicity in rats: involvement of plasma membrane and calcium homeostasis in protective effect. Methods Find Exp Clin Pharmacol. 1986;8(8):469-77.
[20] Dozmorov IM, Kuzin II, Lutsan NI, Lutsenko GV, Prokhorova AL, Sapozhnikov AM, Andronova TM, Ivanov VT. Study of immunomodulatory properties of N-acetylmuramyl-L-alanyl-D-isoglutamine and N-acetylglucosaminyl-(beta 1----4)-N-acetylmuramyl-L-alanyl-D-isoglutamine. Biomed Sci. 1991;2(6):651-8.
[21] Ivanov VT, Khaitov RM, Andronov TM, Pinegin BV. Likopid - new highly efficient domestic immunomodulator for the treatment and prevention of diseases associated with secondary immune deficiency. Immunology. 1996; 3:49-53.
[22] Dziarski R. Recognition of bacterial peptidoglycan by the innate immune system. Cell Mol Life Sci. 2003;60(9):1793-804.
[23] Steiner H. Peptidoglycan recognition proteins: on and off switches for innate immunity. Immunol Rev. 2004;198:83-96.
[24] Dziarski R. Peptidoglycan recognition proteins (PGRPs). Mol Immunol. 2004;40(12):877-86.
[25] Fournier B., Philpott D. J. Recognition of Staphylococcus aureus by the innate immune system. Clin Microbiol Rev. 2005;18(3):521-40.
[26] Girardin SE, Philpott DJ. Mini-review: the role of peptidoglycan recognition in innate immunity. Eur J Immunol. 2004;34(7):1777-82.
[27] Kufer TA, Banks DJ, Philpott DJ. Innate immune sensing of microbes by Nod proteins. Ann N Y Acad Sci. 2006;1072:19-27.
[28] Liang MD, Bagchi A, Warren HS, Tehan MM, Trigilio JA, Beasley-Topliffe LK, Tesini BL, Lazzaroni JC, Fenton MJ, Hellman J. Bacterial peptidoglycan-associated lipoprotein: a naturally occurring toll-like receptor 2 agonist that is shed into serum and has synergy with lipopolysaccharide. J Infect Dis. 2005;191(6):939-48.
[29] Nakao Y, Funami K, Kikkawa S, Taniguchi M, Nishiguchi M, Fukumori Y, Seya T, Matsumoto M. Surface-expressed TLR6 participates in the recognition of diacylated lipopeptide and peptidoglycan in human cells. J Immunol. 2005;174(3):1566-73.
[30] Uehori J, Matsumoto M, Tsuji S, Akazawa T, Takeuchi O, Akira S, Kawata T, Azuma I, Toyoshima K, Seya T. Simultaneous blocking of human Toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus Calmette-Gu?rin peptidoglycan. Infect Immun. 2003;71(8):4238-49.
[31] Travassos LH, Girardin SE, Philpott DJ, Blanot D, Nahori MA, Werts C, Boneca IG. Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep. 2004;5(10):1000-6.
[32] Triantafilou K, Triantafilou M, Dedrick RL. Interactions of bacterial lipopolysaccharide and peptidoglycan with a 70 kDa and an 80 kDa protein on the cell surface of CD14+ and CD14- cells. Hum Immunol. 2001;62(1):50-63.
[33] Takada H, Yokoyama S, Yang S. Enhancement of endotoxin activity by muramyldipeptide. J Endotoxin Res. 2002;8(5):337-42.
[34] Leemans JC, Vervoordeldonk MJ, Florquin S, van Kessel KP, van der Poll T. Differential role of interleukin-6 in lung inflammation induced by lipoteichoic acid and peptidoglycan from Staphylococcus aureus. Am J Respir Crit Care Med. 2002;165(10):1445-50.
[35] Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol. 2006;6(1):9-20.
[36] Antonov VV, Kozlov VK. Extracellular and cellular mechanisms of general immunosuppression and immune resistance. Cytokines and Inflammation. 2004; 3 (1):8-19.
[37] Pasare C, Medzhitov R. Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol. 2005;560:11-8.
[38] Peng SL. Signaling in B cells via Toll-like receptors. Curr Opin Immunol. 2005;17(3):230-6.
[39] Xu D, Komai-Koma M, Liew FY. Expression and function of Toll-like receptor on T cells. Cell Immunol. 2005;233(2):85-9.
[40] O'Connor GM, Hart OM, Gardiner CM. Putting the natural killer cell in its place. Immunology. 2006;117(1):1-10.
[41] Sivori S, Carlomagno S, Moretta L, Moretta A. Comparison of different CpG oligodeoxynucleotide classes for their capability to stimulate human NK cells. Eur J Immunol. 2006;36(4):961-7.
[42] Myhre AE, Stuestol JF, Dahle MK, Overland G, Thiemermann C, Foster SJ, Lilleaasen P, Aasen AO, Wang JE. Organ injury and cytokine release caused by peptidoglycan are dependent on the structural integrity of the glycan chain. Infect Immun. 2004;72(3):1311-7.
[43] Zhang X, Kimura Y, Fang C, Zhou L, Sfyroera G, Lambris JD, Wetsel RA, Miwa T, Song WC. Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood. 2007;110(1):228-36.
[44] Lambris JD, Allen JB, Schwab JH. In vivo changes in complement induced with peptidoglycan-polysaccharide polymers from streptococcal cell walls. Infect Immun. 1982;35(1):377-80.
[45] Myhre AE, Aasen AO, Thiemermann C, Wang JE. Peptidoglycan--an endotoxin in its own right? Shock. 2006;25(3):227-35.
[46] During K, Porsch P, Mahn A, Brinkmann O, Gieffers W. The non-enzymatic microbicidal activity of lysozymes. FEBS Lett. 1999;449(2-3):93-100.
[47] de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174(5):1209-20.
[48] Hoffmann E, Dittrich-Breiholz O, Holtmann H, Kracht M. Multiple control of interleukin-8 gene expression. J Leukoc Biol. 2002;72(5):847-55.
[49] Myhre AE, Stuestol JF, Dahle MK, Overland G, Thiemermann C, Foster SJ, Lilleaasen P, Aasen AO, Wang JE. Organ injury and cytokine release caused by peptidoglycan are dependent on the structural integrity of the glycan chain. Infect Immun. 2004;72(3):1311-7.
[50] Bera A, Biswas R, Herbert S, Kulauzovic E, Weidenmaier C, Peschel A, Gotz F. Influence of wall teichoic acid on lysozyme resistance in Staphylococcus aureus. J Bacteriol. 2007;189(1):280-3.
[51] Nash JA, Ballard TN, Weaver TE, Akinbi HT. The peptidoglycan-degrading property of lysozyme is not required for bactericidal activity in vivo. J Immunol. 2006;177(1):519-26.
[52] Kumar A, Zhang J, Yu FS. Innate immune response of corneal epithelial cells to Staphylococcus aureus infection: role of peptidoglycan in stimulating proinflammatory cytokine secretion. Invest Ophthalmol Vis Sci. 2004;45(10):3513-22.
[53] Reikeras O, Wang JE, Foster SJ, Utvag SE. Staphylococcus aureus peptidoglycan impairs fracture healing: an experimental study in rats. J Orthop Res. 2007;25(2):262-6.
[54] Il'inskaya A. N., Pichugina L. V., Oliferuk N. S., L'vov V. L., Pinegin B. V. Component of bacterial peptidoglycan as macrophage maturation factor. Immunologiia. 2005; 1:12-15.
[55] Zeisberger E, Roth J. Tolerance to pyrogens. Ann N Y Acad Sci. 1998;856:116-31.
[56] Muhvic D, El-Samalouti V, Flad HD, Radosevic-Stasic B, Rukavina D. The involvement of CD14 in the activation of human monocytes by peptidoglycan monomers. Mediators Inflamm. 2001;10(3):155-62.
[57] Tsuchiya K, Toyama K, Tsuprun V, Hamajima Y, Kim Y, Ondrey FG, Lin J. Pneumococcal peptidoglycan-polysaccharides induce the expression of interleukin-8 in airway epithelial cells by way of nuclear factor-kappaB, nuclear factor interleukin-6, or activation protein-1 dependent mechanisms. Laryngoscope. 2007;117(1):86-91.
[58] Dranoff G. Tumor immunology: immune recognition and tumor protection. Curr. Opin. Immunol. 2002; 14(2):161–164.
[59] Andronov TM, I. M Dozmorov Mustafayev MI Synthetic immunomodulators. Moscow: Nauka, 1991. 199p.
[60] Setdikova N. KH., Borisova A. M., Shul'zhenko A. Ye., Tverskoy K. A., Golubeva N. M., Andronova T. M., Pinegin B. V. Impact of the new immunostimulant glycopin health status and some immunological status of health volunteers. Immunology. 1995; 2:49-52.
[61] Khaitov R. M., Pinegin B. V., Butakov A. A., Andronova T. M., Bulanova Ye. G., Budagyan V. A. Immunotherapy infectious postoperative complications with the new immunostimulant glycopin. Immunology. 1994. 2:47-50.
[62] Pluddemann A, Mukhopadhyay S, Gordon S. The interaction of macrophage receptors with bacterial ligands. Expert Rev Mol Med. 2006;8(28):1-25.
[63] Inamura S, Fujimoto Y, Kawasaki A, Shiokawa Z, Woelk E, Heine H, Lindner B, Inohara N, Kusumoto S, Fukase K. Synthesis of peptidoglycan fragments and evaluation of their biological activity. Org Biomol Chem. 2006;4(2):232-42.
[64] Nowicki A, Szenajch J, Ostrowska G, Wojtowicz A, Wojtowicz K, Kruszewski AA, Maruszynski M, Aukerman SL, Wiktor-Jedrzejczak W. Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int J Cancer. 1996;65(1):112-9.
[65] Ohkuni H, Norose Y, Ohta M, Hayama M, Kimura Y, Tsujimoto M, Kotani S, Shiba T, Kusumoto S, Yokogawa K, Kawata S. Adjuvant activities in production of reaginic antibody by bacterial cell wall peptidoglycan or synthetic N-acetylmuramyl dipeptides in mice. Infect Immun. 1979;24(2):313-8.
[66] Kato I, Canzian F, Plummer M, Franceschi S, van Doorn LJ, Vivas J, Lopez G, Lu Y, Gioia-Patricola L, Severson RK, Schwartz AG, Munoz N. Polymorphisms in genes related to bacterial lipopolysaccharide/peptidoglycan signaling and gastric precancerous lesions in a population at high risk for gastric cancer. Dig Dis Sci. 2007;52(1):254-61.
[67] Lin EY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001;193(6):727-40.
[68] Mackenzie I, Rous P. The experimental disclosure of latent states: a study of the tartow or of rabbits. Exp. Med. 2001. N 48: 365–389.
[69] Lyashenko V. A., Vorob'yev A. A. Molecular basis of immunogenicity of antigens. M.: Meditsina, 1988. 240 p.
[70] Zemskov V. M. Nonspecific immunostimulants. Usp Sovrem Biol. 1991. 3:444–459.
[71] Heymer B. Biological properties of the peptidoglycan. Z Immunitatsforsch Exp Klin Immunol. 1975;149(2-4):245-57.
[72] Sava G, Tomasic J, Hrsak I. Antitumor and antimetastatic activity of the immunoadjuvant peptidoglycan monomer PGM in mice bearing MCa mammary carcinoma. Cancer Immunol Immunother. 1984;18(1):49-53.
[73] Rakhmilevich AL. Bacterial immunomodulators in experimental immunology. Usp Sovrem Biol. 1990; 109(3):379–92.
[74] Hrsak I, Tomasic J, Osmak M. Immunotherapy of B-16 melanoma with peptidoglycan monomer. Eur J Cancer Clin Oncol. 1983;19(5):681-6.
[75] Fiers W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS Lett. 1991;285(2):199-212.