Abstract
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 CO2 concentrations poorly compared to clinical isolates and that CO2 tolerance correlates well with the ability of the isolates to cause disease in mammals. Initial experiments also suggest that CO2 tolerance is particularly important for dissemination of C. neoformans from the lung to the brain. Furthermore, CO2 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 CO2 may improve the correlation between in vitro azole activity and patient outcome.IMPORTANCE A number of studies comparing either patient outcomes or model system virulence across large collections of Cryptococcus isolates have found significant heterogeneity in virulence even among strains with highly related genotypes. Because this heterogeneity cannot be explained by variations in the three well-characterized virulence traits (growth at host body temperature, melanization, and polysaccharide capsule formation), it has been widely proposed that additional C. neoformans virulence traits must exist. The natural niche of C. neoformans is in the environment, where the carbon dioxide concentration is very low (∼0.04%); in contrast, mammalian host tissue carbon dioxide concentrations are 125-fold higher (5%). We have found that the ability to grow in the presence of 5% carbon dioxide distinguishes low-virulence strains from high-virulence strains, even those with a similar genotype. Our findings suggest that carbon dioxide tolerance is a previously unrecognized virulence trait for C. neoformans.
Highlights
IMPORTANCE A number of studies comparing either patient outcomes or model system virulence across large collections of Cryptococcus isolates have found significant heterogeneity in virulence even among strains with highly related genotypes
Recent estimates indicate that 223,000 new cases of causes meningoencephalitis (CME) occur each year with an annual mortality of 181,000 [1]; the majority of CME disease affects people infected with HIV [2]
Like the work of Litvintseva and Mitchell [4], extensive phenotyping of the strains did not reveal an in vitro phenotype that correlated with virulence [5]. These data strongly indicate that uncharacterized virulence properties beyond the “big three” of host body temperature tolerance, melanization, and capsule formation play an important role in determining the virulence potential of a given cryptococcal strain [6]
Summary
IMPORTANCE A number of studies comparing either patient outcomes or model system virulence across large collections of Cryptococcus isolates have found significant heterogeneity in virulence even among strains with highly related genotypes. These data strongly indicate that uncharacterized virulence properties beyond the “big three” of host body temperature tolerance, melanization, and capsule formation play an important role in determining the virulence potential of a given cryptococcal strain [6]. Tolerance of host CO2 concentrations seemed to us a potentially important independent trait of C. neoformans strains that cause disease in mammals.
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