Phosphate Induces a Morphological Shift that Enhances Vascular Dissemination of Cryptococcus neoformans

Phenotypic heterogeneity is a common microbial strategy to improves fitness in fluctuating environments. The fungal pathogen Cryptococcus neoformans exhibits dramatic size heterogeneity: it varies from 2-100 μm in diameter during mammalian infection. Following pulmonary invasion, cells enlarge to >30 μm diameter, then decrease over disease course. Extrapulmonary organs, particularly the brain, contain uniformly small cells, implying that that morphotype is important for dissemination. To test this hypothesis, we isolated size-based ex vivo cell populations directly from mouse lungs. Small ex vivo cells readily disseminated compared with other ex vivo populations, small beads, and in vitro-grown small cells. The latter two groups are close in size to small ex vivo cells, suggesting that while size is important, fungal-specific elements also drive extrapulmonary dissemination. We found that mannose exposure facilitates host cell interaction and organ uptake. Phosphate induces small cell formation. This demonstrates how environmental cues shift phenotypic heterogeneity to drive pathogenesis.