Cryptococcus neoformansinteractions with amoebae suggest an explanation for its virulence and intracellular pathogenic strategy in macrophages

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Abstract
Cryptococcus neoformans(Cn) is a soil fungus that causes life-threatening meningitis in immunocompromised patients and is a facultative intracellular pathogen capable of replication inside macrophages. The mechanism by which environmental fungi acquire and maintain virulence for mammalian hosts is unknown. We hypothesized that the survival strategies forCnafter ingestion by macrophages and amoebae were similar. Microscopy, fungal and amoebae killing assays, and phagocytosis assays revealed thatCnis phagocytosed by and replicates inAcanthamoeba castellanii, which leads to death of amoebae. An acapsular strain ofCndid not survive when incubated with amoebae, but melanization protected these cells against killing by amoebae. A phospholipase mutant had a decreased replication rate in amoebae compared with isogenic strains. These observations suggest that cryptococcal characteristics that contribute to mammalian virulence also promote fungal survival in amoebae. Intracellular replication was accompanied by the accumulation of polysaccharide containing vesicles similar to those described inCn-infected macrophages. The results suggest that the virulence ofCnfor mammalian cells is a consequence of adaptations that have evolved for protection against environmental predators such as amoebae and provide an explanation for the broad host range of this pathogenic fungus.