Microbial glycolipids: possible virulence factors that scavenge oxygen radicals.

Two important pathogens of developing countries, Mycobacterium leprae, the etiologic agent of leprosy, and Leishmania donovani, the protozoal parasite that causes kalaazar, persist in the human host primarily in mononuclear phagocytes. The mechanisms by which they survive in these otherwise highly cytocidal cells are presently unknown. Since the best understood cytocidal mechanism of these cells is the oxygen-dependent system that provides lethal oxidants including the superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH), and singlet oxygen (1O2), we sought specific microbial products of these organisms that might enable them to elude oxidative cytocidal mechanisms. Phenolic glycolipid I of M. leprae and lipophosphoglycan of L. donovani are unique cell-wall-associated glycolipids produced in large amounts by the organisms. In this study, phenolic glycolipid I derivatives and lipophosphoglycan were examined for their ability to scavenge potentially cytocidal oxygen metabolites in vitro. Electron spin resonance and spin-trapping indicate that phenolic glycolipid I derivatives and lipophosphoglycan are highly effective in scavenging hydroxyl radicals and superoxide anions. The results suggest that complex glycolipids and carbohydrates of intracellular pathogens that can scavenge oxygen radicals may contribute to their pathogenicity and virulence.

Oxygen metabolism in phagocytes of leprotic patients: enhanced endogenous superoxide dismutase activity and hydroxyl radical generation by clofazimine.

We examined the generation of active oxygens (O2-, H2O2, and OH X ) and the superoxide dismutase (SOD) activity of polymorphonuclear leukocytes (PMNs) and monocytes from 14 leprotic patients manifesting a bacillary index above 2.2. Patients with disease of more than 4 years in duration showed significantly enhanced SOD activity and a decrease in O2- and OH X production. The antileprotic agent, clofazimine, significantly increased the generation of OH X in a dose-dependent manner, with a subsequent decrease in H2O2, but had no effect on the SOD activity of the PMNs and monocytes. In medium containing FeSO4 or Fe2+-EDTA, the drug elevated OH X production markedly further. Phagocytic SOD in PMNs and monocytes of leprotic patients was both host and bacillus derived, because the presence of cyanide, to which human-derived cuprozinc SOD is susceptible, did not completely abrogate SOD activity. The difficulty in treating leprosy may be partly ascribable to decreased phagocytic OH X generation, which in leprosy patients is apparently due to the uptake of Hansen bacillus-derived SOD. Clofazimine may be effective in leprosy by chelating Fe2+, with the resultant potentiation of the catalyzing activity of Fe2+ in the Haber-Weiss reaction increasing OH X formation from H2O2.