Microevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>

ABSTRACT Passage in mice of opportunistic pathogens such as Cryptococcus neoformans is known to increase virulence, but little is known about the molecular mechanisms involved in virulence adaptation. Serial mouse passage of nine environmental strains of serotype A C. neoformans identified two highl...

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Autores principales:	Guowu Hu, Shu Hui Chen, Jin Qiu, John E. Bennett, Timothy G. Myers, Peter R. Williamson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/22e8109560514a0c9e4df231069c035e
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spelling	oai:doaj.org-article:22e8109560514a0c9e4df231069c035e2021-11-15T15:45:13ZMicroevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>10.1128/mBio.00941-142150-7511https://doaj.org/article/22e8109560514a0c9e4df231069c035e2014-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00941-14https://doaj.org/toc/2150-7511ABSTRACT Passage in mice of opportunistic pathogens such as Cryptococcus neoformans is known to increase virulence, but little is known about the molecular mechanisms involved in virulence adaptation. Serial mouse passage of nine environmental strains of serotype A C. neoformans identified two highly adapted virulent strains that showed a 4-fold reduction in time to death after four passages. Transcriptome sequencing expression studies demonstrated increased expression of a FRE3-encoded iron reductase in the two strains but not in a control strain that did not demonstrate increased virulence during mouse passage. FRE3 was shown to express an iron reductase activity and to play a role in iron-dependent growth of C. neoformans. Overexpression of FRE3 in the two original environmental strains increased growth in the macrophage cell line J774.16 and increased virulence. These data demonstrate a role for FRE3 in the virulence of C. neoformans and demonstrate how the increased expression of such a “virulence acquisition gene” during the environment-to-mammal transition, can optimize the virulence of environmental strains in mammalian hosts. IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that also resides in the environment. Recent studies have suggested that the organism may undergo microevolution in the host. However, little is known about the permitted genetic changes facilitating the adaptation of environmental strains to mammalian hosts. The present studies subjected environmental strains isolated from several metropolitan areas of the United States to serial passages in mice. Transcriptome sequencing expression studies identified the increased expression of an iron reductase gene, FRE3, in two strains that adapted in mice to become highly virulent, and overexpression of FRE3 recapitulated the increased virulence after mouse passage. Iron reductase in yeast is important to iron uptake in a large number of microbial pathogens. These studies demonstrate the capacity of C. neoformans to show reproducible changes in the expression levels of small numbers of genes termed “virulence adaptation genes” to effectively increase pathogenicity during the environment-to-mammal transition.Guowu HuShu Hui ChenJin QiuJohn E. BennettTimothy G. MyersPeter R. WilliamsonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 2 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Guowu Hu Shu Hui Chen Jin Qiu John E. Bennett Timothy G. Myers Peter R. Williamson Microevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
description	ABSTRACT Passage in mice of opportunistic pathogens such as Cryptococcus neoformans is known to increase virulence, but little is known about the molecular mechanisms involved in virulence adaptation. Serial mouse passage of nine environmental strains of serotype A C. neoformans identified two highly adapted virulent strains that showed a 4-fold reduction in time to death after four passages. Transcriptome sequencing expression studies demonstrated increased expression of a FRE3-encoded iron reductase in the two strains but not in a control strain that did not demonstrate increased virulence during mouse passage. FRE3 was shown to express an iron reductase activity and to play a role in iron-dependent growth of C. neoformans. Overexpression of FRE3 in the two original environmental strains increased growth in the macrophage cell line J774.16 and increased virulence. These data demonstrate a role for FRE3 in the virulence of C. neoformans and demonstrate how the increased expression of such a “virulence acquisition gene” during the environment-to-mammal transition, can optimize the virulence of environmental strains in mammalian hosts. IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that also resides in the environment. Recent studies have suggested that the organism may undergo microevolution in the host. However, little is known about the permitted genetic changes facilitating the adaptation of environmental strains to mammalian hosts. The present studies subjected environmental strains isolated from several metropolitan areas of the United States to serial passages in mice. Transcriptome sequencing expression studies identified the increased expression of an iron reductase gene, FRE3, in two strains that adapted in mice to become highly virulent, and overexpression of FRE3 recapitulated the increased virulence after mouse passage. Iron reductase in yeast is important to iron uptake in a large number of microbial pathogens. These studies demonstrate the capacity of C. neoformans to show reproducible changes in the expression levels of small numbers of genes termed “virulence adaptation genes” to effectively increase pathogenicity during the environment-to-mammal transition.
format	article
author	Guowu Hu Shu Hui Chen Jin Qiu John E. Bennett Timothy G. Myers Peter R. Williamson
author_facet	Guowu Hu Shu Hui Chen Jin Qiu John E. Bennett Timothy G. Myers Peter R. Williamson
author_sort	Guowu Hu
title	Microevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_short	Microevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_full	Microevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_fullStr	Microevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_full_unstemmed	Microevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_sort	microevolution during serial mouse passage demonstrates <italic toggle="yes">fre3</italic> as a virulence adaptation gene in <named-content content-type="genus-species">cryptococcus neoformans</named-content>
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/22e8109560514a0c9e4df231069c035e
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Microevolution During Serial Mouse Passage Demonstrates <italic toggle="yes">FRE3</italic> as a Virulence Adaptation Gene in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>

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