CHLOROQUINE INDUCES HUMAN MONONUCLEAR PHAGOCYTES TO INHIBIT AND KILL CRYPTOCOCCUS-NEOFORMANS BY A MECHANISM INDEPENDENT OF IRON DEPRIVATION

Infections due to Cryptococcus neoformans are common in AIDS patients. We investigated the effect of chloroquine, which raises the pH of pha golysosomes, on the anticryptococcal activity of mononuclear phagocyte s, C, neoformans multiplied within monocyte-derived macrophages (MDM) in the absence of chloroquine but were killed with the addition of chl oroquine. Ammonium chloride was also beneficial, suggesting that effec ts were mediated by alkalinizing the phagolysosome, Chloroquine inhibi ts growth of other intracellular pathogens by limiting iron availabili ty, However, chloroquine-induced augmentation of MDM anticryptococcal activity was unaffected by iron nitriloacetate, demonstrating that chl oroquine worked by a mechanism independent of iron deprivation. There was an inverse correlation between growth of C. neoformans in cell-fre e media and pH, suggesting that some of the effect of chloroquine on t he anticryptococcal activity of MDM could be explained by relatively p oor growth at higher pH, Chloroquine enhanced MDM anticryptococcal act ivity against all tested cryptococcal strains except for one large-cap sule strain which was not phagocytosed, Positive effects of chloroquin e mere also seen in monocytes from both HIV-infected and -uninfected d onors, Finally, chloroquine was therapeutic in experimental cryptococc osis in outbred and severe combined immunodeficient mice. Thus, chloro quine enhances the activity of mononuclear phagocytes against C. neofo rmans by iron-independent, pH-dependent mechanisms and is therapeutic in murine models of cryptococcosis, Chloroquine might have clinical ut ility for the prophylaxis and treatment of human cryptococcosis.