Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii

The pathogenic yeast Cryptococcus gattii, which is causing an outbreak in the Pacific Northwest region of North America, causes life-threatening pulmonary infections and meningoencephalitis in healthy individuals, unlike Cryptococcus neoformans, which commonly infects immunocompromised patients. In...

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Main Authors:	Chen, Ying-Lien, Lehman, Virginia N., Lewit, Yonathan, Averette, Anna F., Heitman, Joseph
Format:	Online
Language:	English
Published:	Genetics Society of America 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583459/

id	pubmed-3583459
recordtype	oai_dc
spelling	pubmed-35834592013-03-01 Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii Chen, Ying-Lien Lehman, Virginia N. Lewit, Yonathan Averette, Anna F. Heitman, Joseph Investigations The pathogenic yeast Cryptococcus gattii, which is causing an outbreak in the Pacific Northwest region of North America, causes life-threatening pulmonary infections and meningoencephalitis in healthy individuals, unlike Cryptococcus neoformans, which commonly infects immunocompromised patients. In addition to a greater predilection for C. gattii to infect healthy hosts, the C. gattii genome sequence project revealed extensive chromosomal rearrangements compared with C. neoformans, showing genomic differences between the two Cryptococcus species. We investigated the roles of C. gattii calcineurin in three molecular types: VGIIa (R265), VGIIb (R272), and VGI (WM276). We found that calcineurin exhibits a differential requirement for growth on solid medium at 37°, as calcineurin mutants generated from R265 were more thermotolerant than mutants from R272 and WM276. We demonstrated that tolerance to calcineurin inhibitors (FK506, CsA) at 37° is linked with the VGIIa molecular type. The calcineurin mutants from the R272 background showed the most extensive growth and morphological defects (multivesicle and larger ring-like cells), as well as increased fluconazole susceptibility. Our cellular architecture examination showed that C. gattii and C. neoformans calcineurin mutants exhibit plasma membrane disruptions. Calcineurin in the C. gattii VGII molecular type plays a greater role in controlling cation homeostasis compared with that in C. gattii VGI and C. neoformans H99. Importantly, we demonstrate that C. gattii calcineurin is essential for virulence in a murine inhalation model, supporting C. gattii calcineurin as an attractive antifungal drug target. Genetics Society of America 2013-03-01 /pmc/articles/PMC3583459/ /pubmed/23450261 http://dx.doi.org/10.1534/g3.112.004242 Text en Copyright © 2013 Chen et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Chen, Ying-Lien Lehman, Virginia N. Lewit, Yonathan Averette, Anna F. Heitman, Joseph
spellingShingle	Chen, Ying-Lien Lehman, Virginia N. Lewit, Yonathan Averette, Anna F. Heitman, Joseph Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii
author_facet	Chen, Ying-Lien Lehman, Virginia N. Lewit, Yonathan Averette, Anna F. Heitman, Joseph
author_sort	Chen, Ying-Lien
title	Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii
title_short	Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii
title_full	Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii
title_fullStr	Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii
title_full_unstemmed	Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii
title_sort	calcineurin governs thermotolerance and virulence of cryptococcus gattii
description	The pathogenic yeast Cryptococcus gattii, which is causing an outbreak in the Pacific Northwest region of North America, causes life-threatening pulmonary infections and meningoencephalitis in healthy individuals, unlike Cryptococcus neoformans, which commonly infects immunocompromised patients. In addition to a greater predilection for C. gattii to infect healthy hosts, the C. gattii genome sequence project revealed extensive chromosomal rearrangements compared with C. neoformans, showing genomic differences between the two Cryptococcus species. We investigated the roles of C. gattii calcineurin in three molecular types: VGIIa (R265), VGIIb (R272), and VGI (WM276). We found that calcineurin exhibits a differential requirement for growth on solid medium at 37°, as calcineurin mutants generated from R265 were more thermotolerant than mutants from R272 and WM276. We demonstrated that tolerance to calcineurin inhibitors (FK506, CsA) at 37° is linked with the VGIIa molecular type. The calcineurin mutants from the R272 background showed the most extensive growth and morphological defects (multivesicle and larger ring-like cells), as well as increased fluconazole susceptibility. Our cellular architecture examination showed that C. gattii and C. neoformans calcineurin mutants exhibit plasma membrane disruptions. Calcineurin in the C. gattii VGII molecular type plays a greater role in controlling cation homeostasis compared with that in C. gattii VGI and C. neoformans H99. Importantly, we demonstrate that C. gattii calcineurin is essential for virulence in a murine inhalation model, supporting C. gattii calcineurin as an attractive antifungal drug target.
publisher	Genetics Society of America
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583459/
_version_	1611957914301366272

Calcineurin Governs Thermotolerance and Virulence of Cryptococcus gattii

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