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  • Immunological Properties of Trehalose Dimycolate (Cord Factor) and Other Mycolic Acid-Containing Glycolipids - A Review

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    Immunological properties of trehalose dimycolate (cord factor) and other mycolic acid-containing glycolipids--a review

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    Immunological Properties of Trehalose Dimycolate (Cord Factor) and Other Mycolic Acid-Containing Glycolipids - A Review

    Uploaded by

    Pritha Bhuwapaksophon

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    © All Rights Reserved
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    Microbiol. Immunol, 48(12), 801-811, 2001 Minireview Immunological Properties of Trehalose Dimycolate (Cord Factor) and Other Mycolic Acid-Containing Glycolipids—A Review Roland Ryll *"?, Yoshio Kumazawa’, and Ikuya Yano’ Japan BCG Laboratory, Kivose, Tokyo 204-0022, Japan, ‘Department of Biosciences, School of Science, Kitasato Universit Sagamihara, Kanagawa 228-8555, Japan Received October 15, 2001 Abstract: Mycolic acids are characteristic fatty acids of Mycobacteria and are responsible for the wax-like consistence of these microorganisms. Decades of research revealed that mycolic acid-containing glycolipids, in particular trehalose-6,6'-dimycolate (TDM, cord factor) as their best-studied representative, exert a num- ber of immunomodifying effects. They are able to stimulate innate, early adaptive and both humoral and cellular adaptive immunity. Most functions can be associated with their ability to induce a wide range of chemokines (MCP-1, MIP-a, IL-8) and cytokines (e., I-12, IFN-y, TNF-ce IL-4, 1L-6, IL-10). This review tries to link well-known properties of mycolic acid-containing glycolipids, e., stimulation of cellular and humoral immunity, granuloma form: immunology and to give an outlook on pote Key words: Cord factor, Immunomodulation, Interferon, Mycolic ac wycolate, Tumor necrosis factor Introduction Mycolic acids are characteristic a-branched B-hydroxy fatty acids ofthe genus Mycobacterium (74) and related taxa such as Corynebacterium and Nocardia. ‘The com- position of cord factor, probably the most prominent and best-studied mycolic acid-containing compound of, mycobacteria, was determined as 6,6-dimycoloyl-c-0- trehalose in the 1950s (61) (for representative structures ‘of TDM and the main subclasses of mycolic acids deter mined in M. auberculosis see Fig. 1). The purification of intact mycolic acids by gas chromatography was long ‘hampered by their instability at high temperatures, which causes cleavage of the branched molecule into two frag- ments, This problem was overcome by the introduction of trimethylsilylation as stabilizing modification, which allowed the powerful combination of gas chromatogra- phy, followed by structural fine analysis of purified, Lniragmented molecules by mass spectrometry (94-96). “Address correspondence 10 Dr, Roland Ryll, Japan BCG Laboratory, 3-1-5 Matsuyama, Kiyose, Tokyo 204-0022, Japan. Fax: +817424-92-9391. E-mail: ryl@ jet sei. kitasatovu.ae.jp (or jbeglab@din.orjp) Bol n and anti-tumor activity, with recent findings in molecular practical applications. |, Mycobacterium tuberculosis, Trehalose Subsequently, the molecular details of mycolic acids derived from many species and strains have been ana- lyzed by mass spectrometry as well as nuclear magnetic resonance (e-., (59, 91]; for a comprehensive review about the chemistry and biochemistry of mycolic acids refer to [4). In general, an increasing average carbon number of mycolic acids has been determined from Dietzia, Rhodococeus, Nocardia, Gordona to Mycobac- Covalently attached to arabinogalactan, these wall skeleton terium, lipids form an integral part of the (Fig. 2), According to current models of the mycobac terial cell envelope, which are ultimately based on an idea ‘of Minnikin (47; for recent reviews see [12, 14, 15), ara- binogalactan-attached mycolic acids are believed to form one highly-arranged leaflet of a second membrane: Abbreviations: BCG, bacillus Calmette-Guerin: CWS, cell wall skeleton; DC, dendritic cell; ELISA, enzyme-linked immunosorbent assay; GMM, glucose monomycolate; IFN-y, interferon, IL, imerleukin; MCP-1, monocyte chemoattractant protein 1; MIP-1a, mactophage inflammatory protein lo RT PCR, reverse-rnscriptase polymerase chun reaction; TCR, T cel receptor: TDM, trehalose dimycolate; Th, T helper: TNF-c, {tumor necrosis factor es; VEGE, vascular endothelial growth fac- 802 R.RYLLer aL gs Teale 66-dinyesate GH) CH (CHa) sCH-CHICHi) yg HCHOOCH, on H © on on ° on on o hy oH i Ct,OCOCHCHCH:) CH=CH CHa),CHs 1 (Chh)p I ab ct ch On w nN I Ga(CHy rrCIECHUCH gCHFCHNCHa)SCHCHCOO—ormyelie ci Coats ie ae Coben ERENCE CHEECH) CHEICOOH ows mesic cus Cathe ° ak on fo OA i CHyCtiy AE HLICHCHEHCHeCHEHCOOH keto meatal cH Cotes Fig. 1. Representative strictures of TDM and the three main subclasses of mycolic acids to be found in M. tuberculosis. TMT ] cM ] OL 17 stoncnin lipids | MA J meciura- macrophages | Qe ‘Adaptive cellular —>| Na IFN-y eal ae ILD ‘etvation x ‘Natural Anti-tumor — : activity Phago- nitric eytosis oxide ~ kaling y Innate immunity Fig. 3, Immunomodifying properties of TDM, The major elfector molecules and eels are shown, interactions marked by question marks can be inferted from various resuls, but have not been proven dire the past (75). A challenge for the future will be the identification of cord factor-related substances and/or administration protocols, which retain adjuvant activity while concomitantly reducing toxicity and adverse side effects. Preliminary results indicate that this goal may be feasible (Ryll etal, unpublished data). ‘The discovery that mycolic acids evoke antibody responses in mycobacteria infected patients allows the beneficial exploitation of these substances in another clinical context. Antibody titers have been shown to be significantly elevated in patients with active tuberculosis, compared to healthy controls or patients with inactive disease or after chemotherapy (41). Likewise, cord factor-based sero diagnosis has been proven useful for diagnosis of intesti- nal tuberculosis and ocular tuberculosis (31, 80). In addition to detecting active mycobacterial infections, the species specificity of mycolic acids, which in turn is reflected by specific antibodies, allows identification of the infecting mycobacterial species. One study including species-specific cord factors and other glycolipids allowed the discrimination between infection with M. tuberculosis and M. avium, a strain increasingly causing ly opportunistic infection in AIDS patients (18). In the future serodiagnosis including mycoloyl glycolipids as antigens might reliably identify and differentiate active mycobacterial infection by a simple and fast method, which not only can be automated, but also can be offered 410-use kits suitable for on-site testing in deve coping countries. In conclusion, half a century of research has provided ‘numerous insights into the effects of mycolic acid-con- taining glycolipids on the immune system. While many points still require more detailed studies, itis reasonable to assume that the results of previous investigations will soon be used in clinical applications. References 1) Asvelineau, J, and Lanéelle,G. 1998. Myeobucterial lipid: ‘ahistorical perspective, Frontiers Biosci 3: €164-e174, 2) Azuma, I, and Seya,T. 2001, Development of immunoad: juvants or immunesherapy of cancer. Inte. Immunophar rmacol. 1: 1249-125 3) Baars, A., Claessen, AMLE.. van den Eertwegh, AJ-M.. Gall, HE, Stam, G.M., Meier, S., Giaccone, G., Meier, R.RYLL erat CJLM, Scheper, RJ. Wagstaff, Vermorken, LB. and Pinedo, HM. 2000, Skin tests predict survival after autol ‘ogous tumor eell vaccination in metastatic melanoma ‘experience in 81 patients. nt, Oncol, 1: 965-970. Bary, CE. Lee, R.E, Maul, K., Sampson, A.B, Schroe- der, B.G., Slayden, R.A., and Yuan, ¥. 1998, Mycolic acids: structure, biosynthesis and physiological functions Prog. Lipid Res. 37: 143-179, Beckman, E.M., Porcelli,S.A.. Morita, CT, Behar. SM. Furlong, 8.7, and Brenner, M.B. 1994, Recognition of a lipid antigen by CDI-resricted cB" T cells. Nature 372: 691-604, eckierkunst, A. 1968. Acute granulomatous response pro- ‘duced in mice by trehalose-—,6"slimycolate. J. Bacteriol. 96 938-961 Bekierkunst, A.. Levi, LS., and Yarkoni, E. 1971. Sup- pression of urethan-induced lung adenomas in mie weated ‘with trehalose-6,6-dimycolate (con! factor) and living baci lus Calmette Gustin. Science 174: 1240-1242. Bekierkuast, A. Yarkoni, E., Flechner, 1, Morecki, S.. Vilkas, E., and Lederer, E. 1971, Immune response t0 sheep Fed blood cells in mice pretreated with myeobacte~ rial fractions. Infect. Immun, 4: 256-263. Bevilacqua, M.P, 1993, Endothelia-leukoeyte adhesion molecules. Annu, Rey. Immunol, 1: 767-808. Bilsland, C.A., and Milstein, C. 1991. The identification of the B2-microglobulin binding antigen encoded by the hhuman CDID gene. Eur. J. Immunol. 24: 71-78 Blumberg, RS. Gerdes, D. Cot, A., Porelli, SAw and Balk, SP. 1995. Structure and function of the CDI family, ‘of MHC-like cell surface proteins, Immunol, Res, 47: 5= 2, CChatterice,D. 1997. The mycobacterial cell wall: structure, biosynthesis and sites of drug action. Curr. Opin. Chem Biol 1: 579-588, Crowe, LM. Spargo, BJ. loneda, T. Bearman, BLL. and Crowe, JH. 1994 Interaction of cond factor (alpha.alpha’~ trehalose-6,6

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