A dissemination-prone morphotype enhances extrapulmonary organ entry by the fungus Cryptococcus neoformans

SUMMARYEnvironmental pathogens, which move from ecological niches to mammalian hosts, must adapt to dramatically different environments. Microbes that disseminate farther, including the fungal meningitis pathogen Cryptococcus neoformans, require additional adaptation to diverse tissues. When C. neoformans enters the lungs, infecting cells (30 μm diameter), then form a heterogeneous population. The brain contains uniformly small cells (∼7 μm). We demonstrate that formation of a small C. neoformans morphotype – called “seed” cells due to their disseminating ability – is critical for extrapulmonary organ entry. Seed cell formation is triggered by environmental factors, including C. neoformans’ environmental niche, pigeon guano. The underlying trigger, phosphate, can be released by tissue damage, potentially establishing a feed-forward loop of seed cell formation and dissemination. We demonstrate that C. neoformans’ size variation is not just a continuum but inducible subpopulations that change host interactions to facilitate microbe survival and spread.