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PubMed1978

Toxicity of emulsified trehalose-6,6'-dimycolate (cord factor) in mice depends on size distribution of mineral oil droplets.

Toxicity of emulsified trehalose-6,6'-dimycolate administered intravenously into mice depended on the size distribution of the mineral oil droplets. Emulsions containing the greatest number of the largest oil droplets were the most toxic. Emulsions of trehalose-6,6'-dimycolate made with peanut oil or with olive oil were less toxic than those made with mineral oil.

Animals↗
PubMed1981

Proliferative responses of central and peripheral rat lymphocytes elicited by cord factor (trehalose 6,6'-dimycolate).

Cord factor--a mixture of 6,6'-diesters of alpha, alpha-D-trehalose with natural mycolic acids--which is purified from mycobacteria and other microorganisms, is known to have adjuvant activity as well as to enhance nonspecific resistance to infections and tumor development. In this work, trehalose 6,6'-dimycolate (TDM) was found to induce proliferative responses in rat thymus and lymph node cells. With the thymus cells, TDM responses were greater after removal of the adherent cell subpopulation. Consistent with this observation was the finding that addition of phagocytic cells purified from peritoneal or lymph node cell suspensions to nonadherent thymocytes abrogated the response of thymocytes to TDM. With the lymph node cells, the presence or removal of adherent cells had no major consequence on the TDM-induced proliferative response, since similar increases in deoxyribonucleic acid synthesis were observed with unfractionated and nonadherent cells. The difference between the sensitivities of thymus cells and lymph node cells to regulation by adherent cells indicated the existence of more than one type of TDM responder cell in rats. TDM also displayed marked stimulatory activity on thymus and lymph node cells from germ-free rats, ruling out the possibility that TDM might have triggered a specific, secondary, in vitro immune response. Expansion of a selected cell population(s) triggered by TDM may be involved in the manifestation of adjuvant activity and possibly other immunological properties of cord factor.

Animals↗
PubMed1984

Macrophage activation by cord factor (trehalose 6,6'-dimycolate): enhanced association with and intracellular killing of Trypanosoma cruzi.

Cord factor (trehalose 6,6'-dimycolate[TDM] ), a mixture of 6,6'-diesters of alpha, alpha-D-trehalose with natural mycolic acids, has been described as having immunoregulatory and antitumor activities in vivo, although the relevant mechanisms of action remain unelucidated. In this work, we measured the effects of TDM on both mouse macrophage association with (i.e., the combined result of surface binding and uptake) and subsequent intracellular killing of Trypanosoma cruzi, the causative agent of Chagas' disease. Pretreatment of macrophage cultures with TDM for 16 h markedly increased both the ability of these cells to associate with T. cruzi and the rate of killing of parasites. The results obtained with macrophages treated with TDM after exposure to the parasites did not differ from those obtained with untreated macrophages, indicating that macrophage activation did not occur immediately after TDM treatment and was time dependent. The TDM effect was reversible since the extents of macrophage-parasite association and intracellular killing returned to normal levels 4 h after TDM treatment. Neither catalase, which scavenges hydrogen peroxide, nor sodium azide or potassium cyanide, which are inhibitors of peroxidase activity, significantly reduced the level of trypanosome killing by TDM-treated macrophages. TDM also increased the uptake of glutaraldehyde-killed T. cruzi and latex particles, suggesting that TDM could act mostly by enhancing phagocytosis and that increased cell association with the living trypanosomes did not necessarily depend on the macrophages becoming more susceptible to parasite invasion. These results indicate that TDM modulates macrophage function by augmenting both internalization and intracellular destruction. Hydrogen peroxide and peroxidase activity, postulated to be involved in phagocytic killing of T. cruzi, did not appear to be an absolute requirement for the killing of T. cruzi in TDM-treated macrophages.

Animals↗
PubMed1985

Vaccination of rabbits against Entamoeba histolytica with aqueous suspensions of trehalose-dimycolate as the adjuvant.

Rabbits were immunized with soluble Entamoeba histolytica antigen with an aqueous suspension of trehalose-6,6'-dimycolate used as the adjuvant. Induction of protective immunity in the immunized animals was demonstrated by enhanced humoral and cell-mediated immune responses and 100% survival after challenge. Administration of soluble antigen only failed to induce a similar degree of protective immunity. Trehalose-6,6'-dimycolate alone produced only a slight increase in nonspecific resistance.

Adjuvants, Immunologic↗
PubMed1972

Antibody formation to trehalose-6,6'-dimycolate (cord factor) of Mycobacterium tuberculosis.

A complex of trehalose-6, 6'-dimycolate (cord factor) and methylated bovine serum albumin was prepared, and its effect on the toxicity of cord factor in mice was studied. Either the active immunization with cord factor-methylated bovine serum albumin complex or the passive transfer of sera of rabbits vaccinated with the complex protected mice against the toxic action of cord factor. The antisera of mice and rabbits and gamma globulin fraction of rabbit antiserum demonstrated a precipitin reaction with an aqueous emulsion of cord factor. The reactivity of anticord factor was totally lost by treatment with 2-mercaptoethanol. The antigenic determinant group of cord factor was alpha-d-trehalose. Cord factor-anticord factor complex was devoid of activity to induce in vitro swelling and inhibition of respiratory and phosphorylative activity of mouse liver mitochondria. These results suggest that vaccination with cord factor-methylated bovine serum albumin complex induced the production of antibody to cord factor in mouse and rabbit serum which binds to cord factor and neutralizes its toxic activity either in vivo or in vitro.

Animals↗
PubMed1985

Trehalose dimycolate from various mycobacterial species induces differing anti-infectious activities in combination with muramyl dipeptide.

Significant resistance against influenza virus and Mycobacterium tuberculosis infections was induced when trehalose dimycolate from M. tuberculosis or M. bovis but not M. avium was combined with muramyl dipeptide. Trehalose dimycolate from M. tuberculosis, in contrast to that from M. avium, could confer resistance against Toxoplasma gondii infections.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1993

Development of a trehalose 6,6'-dimycolate model which explains cord formation by Mycobacterium tuberculosis.

Trehalose 6,6'-dimycolate (TDM) is a glycolipid of mycobacteria that displays an unusual toxicity and has been reported to be a virulence factor for Mycobacterium tuberculosis. Lack of understanding of the toxicity has impeded acceptance of TDM as a virulence factor. We previously reported that the toxicity of TDM depends on its presentation as a surface monolayer consisting of 30% trehalose and 70% exposed mycolic acid moieties. This paper further investigates the structure of the TDM monolayer. It began with the observation that beads coated with TDM, but not with closely related analogs, aggregate to form organized structures resembling the cords of virulent mycobacteria. This implied that the TDM molecules in the monolayer were arranged in an organized structure. This structure was investigated by real-time kinetic microscopy, scanning electron microscopy, and gross observations of the adhesion patterns of TDM-coated beads. In each of these models, the structures induced by TDM differed from those of analogs or other amphiphiles studied. These observations were used to construct a model of the structure of TDM monolayer which envisions linear arrays of TDM molecules arranged in a circumferential pattern on beads with discontinuities only at the two poles.

Cord Factors↗
PubMed1997

In vivo induction of apoptosis in the thymus by administration of mycobacterial cord factor (trehalose 6,6'-dimycolate).

It is reported that some bacteria or bacterial components cause thymic atrophy via the apoptotic process. The present study demonstrated for the first time in vivo induction of apoptosis in the mouse thymus by mycobacterial cord factor (CF) (trehalose 6,6'-dimycolate). When 300 microg of purified CF from Mycobacterium tuberculosis was intravenously administered to BALB/c mice in the form of water-in-oil-in-water (w/o/w) emulsion, thymic atrophy and pulmonary granulomas were induced with a peak on day 7, whereas, in the form of liposomes, CF induced thymic atrophy on days 14 to 21 in parallel with the development of hepatic granulomas. Thymic atrophy resulted from the depletion of cortical lymphocytes via apoptosis as revealed by DNA fragmentation and karyorrhectic changes. In contrast, mycobacterial sulfatide (2,3,6,6'-tetraacyl trehalose 2'-sulfate) caused neither thymic atrophy nor granuloma formation. Compared to lipopolysaccharide-induced thymocyte apoptosis, CF (w/o/w)-induced thymocyte apoptosis developed more slowly, reached a maximum later, and lasted longer but was less intense. Although serum tumor necrosis factor alpha (TNF-alpha) levels in CF-treated mice were not significantly elevated, administration of anti-TNF-alpha antibody almost completely inhibited thymic atrophy and granuloma formation. Serum corticosterone levels were only slightly elevated by CF administration. The present results indicate that mycobacterial CF induces thymic atrophy via apoptosis, which is closely linked with granuloma formation.

Animals↗
PubMed2005

FbpA-Dependent biosynthesis of trehalose dimycolate is required for the intrinsic multidrug resistance, cell wall structure, and colonial morphology of Mycobacterium smegmatis.

Ligation of mycolic acids to structural components of the mycobacterial cell wall generates a hydrophobic, impermeable barrier that provides resistance to toxic compounds such as antibiotics. Secreted proteins FbpA, FbpB, and FbpC attach mycolic acids to arabinogalactan, generating mycolic acid methyl esters (MAME) or trehalose, generating alpha,alpha'-trehalose dimycolate (TDM; also called cord factor). Our studies of Mycobacterium smegmatis showed that disruption of fbpA did not affect MAME levels but resulted in a 45% reduction of TDM. The fbpA mutant displayed increased sensitivity to both front-line tuberculosis-targeted drugs as well as other broad-spectrum antibiotics widely used for antibacterial chemotherapy. The irregular, hydrophobic surface of wild-type M. smegmatis colonies became hydrophilic and smooth in the mutant. While expression of M. smegmatis fbpA restored defects of the mutant, heterologous expression of the Mycobacterium tuberculosis fbpA gene was less effective. A single mutation in the M. smegmatis FbpA esterase domain inactivated its ability to provide antibiotic resistance. These data show that production of TDM by FbpA is essential for the intrinsic antibiotic resistance and normal colonial morphology of some mycobacteria and support the concept that FbpA-specific inhibitors, alone or in combination with other antibiotics, could provide an effective treatment to tuberculosis and other mycobacterial diseases.

Acyltransferases↗
PubMed1989

[Granuloma formation in mice by liposomes of new glycolipid containing mycolic acids, "trehalose 2,3,6'-trimycolate"].

After intravenous administration of liposomes containing a novel glycolipid, trehalose 2,3,6'-trimycolate, isolated from Rhodococcus aurantiacus, the granuloma formation was observed distinctively in the lungs, spleen and liver of ICR mice. The concentration of the glycolipid in liposomes influenced profoundly on the inducibility for granulomas and the liposomes containing 10 mol% of trehalose 2,3,6'-trimycolate showed the highest activity for the granuloma formation in mice without a significant loss of body weight of mice with a less toxicity. EggPC liposomes are of more highly inducible for the granuloma formation in mice than eggPC:PS (7:3, mol ratio) liposomes or eggPC:Chol (9:1, mol ratio) liposomes, suggesting that cholesterol in liposomes was not necessarily essential for inducing granulomas in mice. Among the various PC liposomes, synthetic dimyristoyl-phosphatidylcholine (DMPC) or dipalmitoylphosphatidylcholine (DPPC) liposomes were of highly inducible, although a high responsiveness was also observed with natural lecithines such as egg or soy PC. However, distearoylphosphatidylcholine (DSPC) liposomes did not show any activity for the granuloma formation in any organs of mice. Organ responsiveness differed significantly in the micelle forms injected. Glycolipid entrapped with eggPC-Chol liposomes showed a lower lung index below 1.0, in contrast to w/o/w micelles containing Freunds' incomplete adjuvant, which showed a higher granuloma formation in the lungs. It was also noted that the toxicity of glycolipid containing liposomes was comparatively lower than the toxicity of glycolipid containing w/o/w micelles, indicating that the liposomes appeared to be more suitable for the induction of the immunomodifying activities of mycolic acid-containing glycolipids than w/o/w micelles.

Animals↗
PubMed2005

Hyper expression of kojibiose phosphorylase gene and trehalose phosphorylase gene from Thermoanaerobacter brockii ATCC35047 in Bacillus subtilis and selaginose synthesis utilizing two phosphorylases.

The kojibiose phosphorylase (KP) gene and trehalose phosphorylase (TP) gene from Thermoanaerobacter brockii ATCC35047 were intracellularly hyper-expressed under the control of the Bacillus amyloliquefaciens alpha-amylase promoter in Bacillus subtilis. The production yields were estimated to be 2.1 g of KP and 4.9 g of TP per liter of medium. Selaginose, non-reducing trisaccharide, was synthesized from trehalose utilizing the recombinant KP and TP from B. subtilis. Selaginose was not hydrolyzed by salivary amylase, artificial gastric juice, pancreatic amylase, or small intestinal enzymes.

Bacillus subtilis↗
PubMed1998

Purification and characterization of trehalose phosphorylase from Catellatospora ferruginea.

Trehalose phosphorylase was purified from the cell extracts of Catellatospora ferruginea. The enzyme had an apparent molecular weight of 400,000 by gel filtration and 98,000 by SDS-PAGE, suggesting that the enzyme was a tetramer. The enzyme was specific for trehalose in phosphorolysis and specific for beta-D-glucose 1-phosphate in synthesis. In addition to D-glucose, D-xylose and D-fucose were also possible sugar acceptors during synthesis. Phosphate ions were a key to the activity and stability of the enzyme, controlling the equilibrium of the reversible reaction and the heat stability of the enzyme. The enzyme was strongly inhibited by p-chloromercuribenzoate and pyridoxal phosphate. The enzyme was inactivated by heat or by storage frozen with ammonium chloride and lithium chloride.

Actinomycetaceae↗
PubMed1986

[Protective effect of trehalose dimycolate in infestation of mice by Trypanosoma musculi].

Trehalose dimycolate (TDM) treated and untreated mice were infected with Trypanosoma musculi. Compared to untreated mice, treated mice exhibited a five fold reduced number of circulating parasites. Untreated infected mice had a splenomegaly but only a slight increase of spleen weight of treated mice was observed. The role of trehalose dimycolate on T. musculi infection, especially via the macrophage is discussed.

Animals↗
PubMed1982

Antitumor activity and hydrogen peroxide release by macrophages elicited by trehalose diesters.

Trehalose diesters (natural 6,6'-trehalose dimycolate from Mycobacterium tuberculosis or synthetic (a 76 carbon atom analogue)), when suspended in water, give stable and well-defined emulsions. These emulsions, injected i.p. in mice significantly limit the growth of P815 syngeneic mastocytoma cells. They elicit macrophages with a cytostatic activity against P815 cells in vitro, strong enough to be expressed at low effector to target ratios (E/T = 1.4) or after a short coincubation period (2 hr). The antitumor potential of these macrophages seems to coincide with their ability to release H2O2 upon pharmacologic triggering. Depressed levels of alkaline phosphodiesterase and beta-galactosidase are proposed as other biochemical markers of cytostatic macrophages.

Animals↗
PubMedDate not supplied

Induction of pulmonary granulomas, macrophage procoagulant activity, and tumor necrosis factor-alpha by trehalose glycolipids.

Trehalose 6,6' dimycolate (TDM), a mycobacterial glycolipid, induces granulomas and hemorrhagic toxic reactions when administered in oil but not as a suspension in saline. It was previously demonstrated by us that TDM forms highly structured layers at oil-water interfaces and then postulated that its toxicity derives from the adhesive properties of these layers. To test this hypothesis, an evaluation was made of the ability of TDM and two analogs, trehalose 6-monomycolate (TMM) and galactose-galactose 6, 6' dimycolate (GDM), to induce pulmonary granulomas and stimulate expression of procoagulant activity (PCA) and tumor necrosis factor-alpha (TNF-alpha). Intravenous injection in mice of oil-in-water emulsions of TDM produced more and larger pulmonary granulomas than injection of TMM or GDM. Similarly, TDM on the surface of beads induced higher levels of PCA and TNF-alpha in human mononuclear cells than the analogs. The correlation of these results with the structure of surface layers of the glycolipids strengthens the hypothesis that the particular surface structure formed by TDM is necessary for its biologic activity.

Animals↗
PubMedDate not supplied

Studies on the toxic effects of quartz and a mycobacterial glycolipid, trehalose 6,6'-dimycolate.

Quartz and trehalose 6,6'-dimycolate (TDM) both potentiate tuberculosis and have toxicities that depend on surface crystalline structures. Investigations were undertaken to determine if TDM can kill macrophages and produce hemolysis in a fashion similar to that of quartz and if quartz can induce granulomas similar to those induced by TDM. Trehalose 6,6'-dimycolate was spread as a molecular monolayer on the surface of tissue culture dishes adjacent to areas of uncoated plastic for comparison. Murine peritoneal macrophages were killed within hours by contact with the TDM monolayer, while those on adjacent areas of uncoated plastic remained viable and spread normally. The membranes of erythrocytes were also damaged by contact with the monolayer of TDM. This damage was inhibited by poly-2-vinyl-pyridine-N-oxide, an inhibitor of hydrogen bonding that blocks quartz induced hemolysis. These data suggest that TDM damages membranes via an adhesive mechanism similar to that of quartz. Furthermore, injections of quartz particles into mice induce acute granulomatous reactions similar to those induced by TDM. These data indicate that TDM and quartz have certain similarities in their mechanisms of action and that these similarities may be of importance in the pathogenesis of tuberculosis.

Animals↗
PubMed1994

IR and Raman spectroscopic studies of the interaction of trehalose with hen egg white lysozyme.

Infrared and Fourier transform Raman spectra are reported for dried mixtures of trehalose and lysozyme. The Raman spectra show effects on the protein amide I band and some sugar bands that are not present when the components are dried separately. Comparison of ir spectra with those published previously show significant differences. It is concluded that these arise because of differences in the extent of drying of the moisture, and that, contrary to some claims, vibrational spectroscopy does not so far show any clear evidence of specific trehalose/protein interactions and that results may be interpreted in terms of entrapment of water within the mixture.

Animals↗