Project Summary Cryptococcus neoformans is a pathogenic fungus, accounting for 181,000 deaths each year, worldwide. After inhalation of C. neoformans, the fungus grows in the lung; if the fungal growth is not controlled in the lung, the fungus can migrate to the central nervous system, causing fatal meningoencephalitis, particularly in immune compromised individuals including HIV/AIDS patients. Cryptococcal meningoencephalitis is a leading cause of HIV/AIDS patients. To cause meningoencephalitis, C. neoformans must invade the brain across the blood-brain barrier and replicate in the brain parenchyma. However, after entering the brain, these invading fungal cells will encounter brain resident macrophages as well as recruited inflammatory monocytes and their derivatives. The outcome of the interactions between C. neoformans and these mononuclear phagocytes will determine the progression of the disease. Thus, the mechanism behind the interactions of C. neoformans with these mononuclear phagocytes is fundamental for understanding cryptococcal pathogenesis. So far, little is known about the interactions between C. neoformans and mononuclear phagocytes in the brain parenchyma after its crossing the blood-brain barrier. Based on our compelling preliminary data, we hypothesize that C. neoformans evolved strategies to escape from host defense and that mononuclear phagocytes orchestrate fungal pathogenesis as well as clearance. By employing genetically engineered C. neoformans strains and their reconstitute strains as well as genetically engineered animals, we will characterize the complex interactions of invading C. neoformans with mononuclear phagocytes and determine how the fungus escapes from host defense in the brain in vivo. If successful, these studies would reveal novel insights into mechanisms of fungal pathogenesis and host-pathogen interactions, providing scientific basis for targeting mononuclear phagocytes aimed at inhibiting fungal growth in the brain.