Host Carbon Dioxide Concentration Is an Independent Stress for Cryptococcus neoformans That Affects Virulence and Antifungal Susceptibility

The ability of Cryptococcus neoformans to cause disease in humans varies significantly among strains with highly related genotypes. In general, environmental isolates of pathogenic species such as Cryptococcus neoformans var. grubii have reduced virulence relative to clinical isolates, despite having no differences in the expression of the canonical virulence traits (high-temperature growth, melanization, and capsule formation). In this observation, we report that environmental isolates of C. neoformans tolerate host CO(2) concentrations poorly compared to clinical isolates and that CO(2) tolerance correlates well with the ability of the isolates to cause disease in mammals. Initial experiments also suggest that CO(2) tolerance is particularly important for dissemination of C. neoformans from the lung to the brain. Furthermore, CO(2) concentrations affect the susceptibility of both clinical and environmental C. neoformans isolates to the azole class of antifungal drugs, suggesting that antifungal testing in the presence of CO(2) may improve the correlation between in vitro azole activity and patient outcome.