Mycobacterium tuberculosis and Mycobacterium leprae, the causative agents of tuberculosis and leprosy, respectively, produce large quantities of lipoarabinomannan (LAM), a highly immunogenic, cell wallassociated glycolipid. This molecule has been previously reported to be a potent inhibitor of gamma interferonmediated activation of murine macrophages. Studies of the mechanism by which this mycobacterial glycolipid down-regulates macrophage effector functions provide evidence that LAM acts at several levels and that it can (i) scavenge potentially cytotoxic oxygen free radicals, (ii) inhibit protein kinase C activity, and (iii) block the transcriptional activation of gamma interferon-inducible genes in human macrophage-like cell lines. These results suggest that LAM can inhibit macrophage activation and triggering and cytocidal activity and that it may represent a chemically defined virulence factor contributing to the persistence of mycobacteria within mononuclear phagocytes.

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A phenolic glycolipid was obtained in high amounts (2% of dry weight) from Mycobacterium leprae isolated from infected armnadillo liver. Infrared and nuclear magnetic resonance spectroscopy showed that it is closely related to "mycoside A" from Mycobacterium kansasii and is therefore a glycosylphenolic phthiocerol diester. The crucial difference between the two products is in the composition of the attached trisaccharide. Gas-liquid chromatography-mass spectroscopy showed that the product from M. kansasii is composed of 2,4-di-0-methylrhamnose, 2-0-methylrhamnose, and 2-0-methylfucose, whereas that from M. leprae contains 2,3-di-0-methylrhamnose, 3-0-methylrhamnose, and 3,6-di-0-methylglucose. The distinct composition of the oligosaccharide segment of the glycolipid from M. leprae may make it useful for the chemical and serological differentiation of this organism from other mycobacteria. Surprisingly large quantities (2.2 mg/ g of dry liver) of the glycolipid were also found in infected liver residue freed of M. leprae, suggesting that it may be responsible for the electron-transparent "foam" surrounding the organism in infected lepromatous tissue.

Snmm~'ySeveral mycobacterial antigens, identified by monoclonal antibodies and patient sera, have been found to be homologous to stress or heat-shock proteins (hsp) defined in Escherichia coli and yeast. A major antigen recognized by most Mycobacterium leprae-reactive human T cell lines and cell wail-reactive T cell clones is a 10-kD protein that has now been cloned and sequenced. The predicted amino acid sequence of this protein is 44% homologous to the hsp 10 (GroES) of E. coll. The purified native and recombinant 10-kD protein was found to be a stronger stimulator of peripheral blood T cell proliferation than other native and recombinant M. l~rae proteins tested. The degree of reactivity parallded the response to intact M. leprae throughout the spectrum of leprosy. Limiting-dilution analysis of peripheral blood lymphocytes from a patient contact and a tuberculoid patient indicated that approximately one third ofM./e~e-reactive T cell precursors responded to the 10-kD antigen. T ceU lines derived from lepromin skin tests were strongly responsive to the 10-kD protein. T cell clones reactive to both the purified native and recombinant 10-kD antigens recognized M. l~rae-specific epitopes as well as epitopes crossreactive with the cognate antigen of M. tuberculosis. Further, the purified hsp 10 elicited strong ddayed-type hypersensitivity reactions in guinea pigs sensitized to M. leprae. The strong T ceil responses against the M. leprae 10-kD protein suggest a role for this heat-shock cognate protein in the protective/resistant responses to infection.

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