Abstract
ABSTRACTThe environmental yeast Cryptococcus neoformans is the most common cause of deadly fungal meningitis in primarily immunocompromised populations. A number of factors contribute to cryptococcal pathogenesis. Among them, inositol utilization has been shown to promote C. neoformans development in nature and invasion of central nervous system during dissemination. The mechanisms of the inositol regulation of fungal virulence remain incompletely understood. In this study, we analyzed inositol-induced capsule growth and the contribution of a unique inositol catabolic pathway in fungal development and virulence. We found that genes involved in the inositol catabolic pathway are highly induced by inositol, and they are also highly expressed in the cerebrospinal fluid of patients with meningoencephalitis. This pathway in C. neoformans contains three genes encoding myo-inositol oxygenases that convert myo-inositol into d-glucuronic acid, a substrate of the pentose phosphate cycle and a component of the polysaccharide capsule. Our mutagenesis analysis demonstrates that inositol catabolism is required for C. neoformans virulence and deletion mutants of myo-inositol oxygenases result in altered capsule growth as well as the polysaccharide structure, including O-acetylation. Our study indicates that the ability to utilize the abundant inositol in the brain may contribute to fungal pathogenesis in this neurotropic fungal pathogen.
Highlights
The environmental yeast Cryptococcus neoformans is the most common cause of deadly fungal meningitis in primarily immunocompromised populations
While no significant difference was observed in a murine intranasal inhalation model, the animal survival data from a murine intravenous injection model showed that C. neoformans cultured in inositol medium exhibited enhanced virulence compared to cells cultured on glucose (Fig. 1C and D)
We observed that yeast cells isolated from infected brain caused lethal infection faster than the ones isolated from infected lung of the same animal (Fig. 1E and F)
Summary
The environmental yeast Cryptococcus neoformans is the most common cause of deadly fungal meningitis in primarily immunocompromised populations. IMPORTANCE The human pathogen Cryptococcus neoformans is the leading cause of fungal meningitis in primarily immunocompromised populations Understanding how this environmental organism adapts to the human host to cause deadly infection will guide our development of novel disease control strategies. Our recent studies revealed that inositol utilization by the fungus promotes C. neoformans development in nature and invasion of the central nervous system during infection. The itr1aD itr3cD mutant has a virulence defect with a reduced ability to penetrate across the blood-brain barrier (BBB), suggesting a role for inositol metabolism in fungal transmigration [13] These studies show the genetic capacity for inositol utilization by C. neoformans and indicate that inositol may affect virulence. These results led us to hypothesize that C. neoformans has developed an efficient inositol sensing and utilization system and employs this inositol utilization system to promote virulence during CNS infection
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