Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box

Key Points Cryptococcus neoformans is generally considered to be an opportunistic pathogen because of its tendency to infect immunocompromised individuals. However, this view has been challenged by recent discoveries of specialized interactions between the fungus and its mammalian hosts, and by the emergence of the related species Cryptococcus gattii as a primary pathogen of immunocompetent populations. Methods have been developed to separate the yeast cells (4–10 μm) from the spores (1–2 μm in diameter) that result from sexual development and meiosis in C. neoformans . The spores are infectious, as has long been suspected, and they are readily phagocytosed by macrophages in the absence of an opsonin, whereas yeast cells require prior opsonization. C. neoformans and C. gattii disseminate from the lung and cross the blood–brain barrier (BBB) to cause meningoencephalitis. The fungal cells cross the BBB directly by transcytosis through endothelial cells lining vessels in the brain, and by a 'Trojan Horse' strategy that involves transport in phagocytic cells. Intracellular cryptococcal cells residing in phagosomes can escape their phagocytic host cells by expulsion and by cell-to-cell transfer between macrophages. Cycles of actin polymerization (actin 'flashes') seem to form transient cages around phagosomes, potentially providing a barrier to expulsion. C. gattii has emerged as a pathogen of immunocompetent humans and animals in western North America. The associated C. gattii strains appear to have a high intracellular proliferation rate in macrophages, and this is correlated with their virulence; they also trigger a reduced protective inflammatory response compared with the response triggered by a representative C. neoformans strain. Giant cells (up to 100 μm) account for ∼20% of the cryptococcal burden during lung infection. These cells are polyploid and resistant to phagocytosis. Studies with fresh isolates of C. neoformans from patients with AIDS revealed that mixed infections, as well as changes in ploidy resulting from endoreplication, are more common during cryptococcosis than previously thought. In addition, clinical isolates and strains that display antifungal-drug resistance can harbour disomic chromosomes. Cryptococcus neoformans is generally considered to be an opportunistic pathogen of immunocompromised individuals. However, as discussed here, this view has been challenged by recent evidence of specialized host–pathogen interactions, and by the e