A mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice

Cryptococcus neoformans: (H99W) was serially passaged in the invertebrate wax moth Galleria mellonella fifteen times to study how fungal virulence evolves under selection and whether those adaptations affect virulence. The G. mellonella passaged strain (P15) and the pre-passage H99W strains were use...

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Autores principales:	Mitch Merryman, Jacob Crigler, Rebecca Seipelt-Thiemann, Erin McClelland
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2020
Materias:	cryptococcus neoformans galleria mellonella serial passage nadh dehydrogenase Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/b4df62b3f98e47f4966ee1d6e9072a9b
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spelling	oai:doaj.org-article:b4df62b3f98e47f4966ee1d6e9072a9b2021-11-17T14:21:59ZA mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice2150-55942150-560810.1080/21505594.2020.1831332https://doaj.org/article/b4df62b3f98e47f4966ee1d6e9072a9b2020-12-01T00:00:00Zhttp://dx.doi.org/10.1080/21505594.2020.1831332https://doaj.org/toc/2150-5594https://doaj.org/toc/2150-5608Cryptococcus neoformans: (H99W) was serially passaged in the invertebrate wax moth Galleria mellonella fifteen times to study how fungal virulence evolves under selection and whether those adaptations affect virulence. The G. mellonella passaged strain (P15) and the pre-passage H99W strains were used to infect three different host models of C. neoformans: C. elegans, G. mellonella, and Balb/c mice. While there was no difference in survival in the invertebrate models, P15 killed mice faster than H99W through both intratracheal and intravenous routes of infection and mice infected intravenously with P15 showed higher fungal burden in the brain. Characterization of the major virulence factors of C. neoformans found that P15 had increased capsule size, GXM release, and melanization. Whole genome sequencing of P15 and H99W revealed two mutations in P15, an insertion in the promoter region of NADH dehydrogenase (CNAG_09000) and an insertion in the LMP1 gene (CNAG_06765). Both ATP production and metabolic rate were higher in P15 compared to H99W. Quantitative RT-PCR suggested that the increased ATP was due to increased RNA levels of NADH dehydrogenase. Thus, adaptation to growth in hemocytes resulted in increased production of ATP, increased metabolic rate, and increased virulence in mice. This was likely due to differential expression of virulence factors, which skewed the host immune response to a less efficient Th2 response, with higher levels of IL-4, IL-10, and TNF-α in the brain. Overall, serial passage experiments have increased our understanding of how this yeast evolves under innate immune selection pressure.Mitch MerrymanJacob CriglerRebecca Seipelt-ThiemannErin McClellandTaylor & Francis Grouparticlecryptococcus neoformansgalleria mellonellaserial passagenadh dehydrogenaseInfectious and parasitic diseasesRC109-216ENVirulence, Vol 11, Iss 1, Pp 1366-1378 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	cryptococcus neoformans galleria mellonella serial passage nadh dehydrogenase Infectious and parasitic diseases RC109-216
spellingShingle	cryptococcus neoformans galleria mellonella serial passage nadh dehydrogenase Infectious and parasitic diseases RC109-216 Mitch Merryman Jacob Crigler Rebecca Seipelt-Thiemann Erin McClelland A mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice
description	Cryptococcus neoformans: (H99W) was serially passaged in the invertebrate wax moth Galleria mellonella fifteen times to study how fungal virulence evolves under selection and whether those adaptations affect virulence. The G. mellonella passaged strain (P15) and the pre-passage H99W strains were used to infect three different host models of C. neoformans: C. elegans, G. mellonella, and Balb/c mice. While there was no difference in survival in the invertebrate models, P15 killed mice faster than H99W through both intratracheal and intravenous routes of infection and mice infected intravenously with P15 showed higher fungal burden in the brain. Characterization of the major virulence factors of C. neoformans found that P15 had increased capsule size, GXM release, and melanization. Whole genome sequencing of P15 and H99W revealed two mutations in P15, an insertion in the promoter region of NADH dehydrogenase (CNAG_09000) and an insertion in the LMP1 gene (CNAG_06765). Both ATP production and metabolic rate were higher in P15 compared to H99W. Quantitative RT-PCR suggested that the increased ATP was due to increased RNA levels of NADH dehydrogenase. Thus, adaptation to growth in hemocytes resulted in increased production of ATP, increased metabolic rate, and increased virulence in mice. This was likely due to differential expression of virulence factors, which skewed the host immune response to a less efficient Th2 response, with higher levels of IL-4, IL-10, and TNF-α in the brain. Overall, serial passage experiments have increased our understanding of how this yeast evolves under innate immune selection pressure.
format	article
author	Mitch Merryman Jacob Crigler Rebecca Seipelt-Thiemann Erin McClelland
author_facet	Mitch Merryman Jacob Crigler Rebecca Seipelt-Thiemann Erin McClelland
author_sort	Mitch Merryman
title	A mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice
title_short	A mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice
title_full	A mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice
title_fullStr	A mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice
title_full_unstemmed	A mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice
title_sort	mutation in c. neoformans mitochondrial nadh dehydrogenase results in increased virulence in mice
publisher	Taylor & Francis Group
publishDate	2020
url	https://doaj.org/article/b4df62b3f98e47f4966ee1d6e9072a9b
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A mutation in C. neoformans mitochondrial NADH dehydrogenase results in increased virulence in mice

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