ENHANCED RESISTANCE TO CRYPTOCOCCUS-NEOFORMANS INFECTION-INDUCED BY CHLOROQUINE IN A MURINE MODEL OF MENINGOENCEPHALITIS

Although the pathogenesis of cerebral cryptococcosis is poorly underst ood, local immune cells, such as microglia and astrocytes, likely play a critical role in containing infection, Chloroquine (CQ) is a weak b ase that accumulates within acidic vacuoles and increases their pH. Co nsequently, proteolytic activity of lysosomal enzymes and intracellula r iron release/availability are impaired, resulting in decreased avail ability of nutrients crucial to microorganism survival and growth in t he host, We found that CQ enhances BV2 microglial-cell-mediated anticr yptococcal activity in vitro, The phenomenon is (i) evident when both unopsonized and opsonized microorganisms are used and (ii) mimicked by NH4Cl, another weak base, and by bafilomycin A(1), an inhibitor of va cuolar-type H+-ATPases. In vivo, intracerebral administration of CQ be fore lethal local challenge with Cryptococcus neoformans results in a significant augmentation of median survival time and a marked reductio n of yeast growth in the brain and is associated with the enhancement of local interleukin 1 beta (IL-1 beta) and 1L-6 mRNA transcripts, Ove rall, these results provide the first evidence that CQ enhances anticr yptococcal host defenses.