Host Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility

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, desp...

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Autores principales:	Damian J. Krysan, Bing Zhai, Sarah R. Beattie, Kara M. Misel, Melanie Wellington, Xiaorong Lin
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Cryptococcus neoformans fluconazole mycology pathogenesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4b040329046441d3861d17cf72848fa2
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spelling	oai:doaj.org-article:4b040329046441d3861d17cf72848fa22021-11-15T16:22:11ZHost Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility10.1128/mBio.01410-192150-7511https://doaj.org/article/4b040329046441d3861d17cf72848fa22019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01410-19https://doaj.org/toc/2150-7511ABSTRACT 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.Damian J. KrysanBing ZhaiSarah R. BeattieKara M. MiselMelanie WellingtonXiaorong LinAmerican Society for MicrobiologyarticleCryptococcus neoformansfluconazolemycologypathogenesisMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cryptococcus neoformans fluconazole mycology pathogenesis Microbiology QR1-502
spellingShingle	Cryptococcus neoformans fluconazole mycology pathogenesis Microbiology QR1-502 Damian J. Krysan Bing Zhai Sarah R. Beattie Kara M. Misel Melanie Wellington Xiaorong Lin Host Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility
description	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.
format	article
author	Damian J. Krysan Bing Zhai Sarah R. Beattie Kara M. Misel Melanie Wellington Xiaorong Lin
author_facet	Damian J. Krysan Bing Zhai Sarah R. Beattie Kara M. Misel Melanie Wellington Xiaorong Lin
author_sort	Damian J. Krysan
title	Host Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility
title_short	Host Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility
title_full	Host Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility
title_fullStr	Host Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility
title_full_unstemmed	Host Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility
title_sort	host carbon dioxide concentration is an independent stress for <named-content content-type="genus-species">cryptococcus neoformans</named-content> that affects virulence and antifungal susceptibility
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/4b040329046441d3861d17cf72848fa2
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Host Carbon Dioxide Concentration Is an Independent Stress for <named-content content-type="genus-species">Cryptococcus neoformans</named-content> That Affects Virulence and Antifungal Susceptibility

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