Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi

ABSTRACT The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. Stress adaptations are especially important for microbial pathogens to respond to rapidly changing conditions, such as those encountered during the transition from the envi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hannah E. Brown, Calla L. Telzrow, Joseph W. Saelens, Larissa Fernandes, J. Andrew Alspaugh
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Cryptococcus neoformans ergosterol fungal genetics membrane pH homeostasis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c647eac886b6428e9f7d9621b131927f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c647eac886b6428e9f7d9621b131927f
record_format	dspace
spelling	oai:doaj.org-article:c647eac886b6428e9f7d9621b131927f2021-11-15T15:56:47ZSterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi10.1128/mBio.00719-202150-7511https://doaj.org/article/c647eac886b6428e9f7d9621b131927f2020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00719-20https://doaj.org/toc/2150-7511ABSTRACT The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. Stress adaptations are especially important for microbial pathogens to respond to rapidly changing conditions, such as those encountered during the transition from the environment to the infected host. Many fungal pathogens have acquired the ability to quickly adapt to changes in extracellular pH to promote their survival in the various microenvironments encountered during a host infection. For example, the fungus-specific Rim/Pal alkaline response pathway has been well characterized in many fungal pathogens, including Cryptococcus neoformans. However, alternative mechanisms for sensing and responding to host pH have yet to be extensively studied. Recent observations from a genetic screen suggest that the C. neoformans sterol homeostasis pathway is required for growth at elevated pH. This work explores interactions among mechanisms of membrane homeostasis, alkaline pH tolerance, and Rim pathway activation. We find that the sterol homeostasis pathway is necessary for growth in an alkaline environment and that an elevated pH is sufficient to induce Sre1 activation. This pH-mediated activation of the Sre1 transcription factor is linked to the biosynthesis of ergosterol but is not dependent on Rim pathway signaling, suggesting that these two pathways are responding to alkaline pH independently. Furthermore, we discover that C. neoformans is more susceptible to membrane-targeting antifungals under alkaline conditions, highlighting the impact of microenvironmental pH on the treatment of invasive fungal infections. Together, these findings further connect membrane integrity and composition with the fungal pH response and pathogenesis. IMPORTANCE The work described here further elucidates how microorganisms sense and adapt to changes in their environment to establish infections in the human host. Specifically, we uncover a novel mechanism by which an opportunistic human fungal pathogen, Cryptococcus neoformans, responds to increases in extracellular pH in order to survive and thrive within the relatively alkaline environment of the human lung. This mechanism, which is intimately linked with fungal membrane sterol homeostasis, is independent of the previously well-studied alkaline response Rim pathway. Furthermore, this ergosterol-dependent alkaline pH response is present in Candida albicans, indicating that this mechanism spans diverse fungal species. These results are also relevant for novel antimicrobial drug development as we show that currently used ergosterol-targeting antifungals are more active in alkaline environments.Hannah E. BrownCalla L. TelzrowJoseph W. SaelensLarissa FernandesJ. Andrew AlspaughAmerican Society for MicrobiologyarticleCryptococcus neoformansergosterolfungal geneticsmembranepH homeostasisMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cryptococcus neoformans ergosterol fungal genetics membrane pH homeostasis Microbiology QR1-502
spellingShingle	Cryptococcus neoformans ergosterol fungal genetics membrane pH homeostasis Microbiology QR1-502 Hannah E. Brown Calla L. Telzrow Joseph W. Saelens Larissa Fernandes J. Andrew Alspaugh Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi
description	ABSTRACT The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. Stress adaptations are especially important for microbial pathogens to respond to rapidly changing conditions, such as those encountered during the transition from the environment to the infected host. Many fungal pathogens have acquired the ability to quickly adapt to changes in extracellular pH to promote their survival in the various microenvironments encountered during a host infection. For example, the fungus-specific Rim/Pal alkaline response pathway has been well characterized in many fungal pathogens, including Cryptococcus neoformans. However, alternative mechanisms for sensing and responding to host pH have yet to be extensively studied. Recent observations from a genetic screen suggest that the C. neoformans sterol homeostasis pathway is required for growth at elevated pH. This work explores interactions among mechanisms of membrane homeostasis, alkaline pH tolerance, and Rim pathway activation. We find that the sterol homeostasis pathway is necessary for growth in an alkaline environment and that an elevated pH is sufficient to induce Sre1 activation. This pH-mediated activation of the Sre1 transcription factor is linked to the biosynthesis of ergosterol but is not dependent on Rim pathway signaling, suggesting that these two pathways are responding to alkaline pH independently. Furthermore, we discover that C. neoformans is more susceptible to membrane-targeting antifungals under alkaline conditions, highlighting the impact of microenvironmental pH on the treatment of invasive fungal infections. Together, these findings further connect membrane integrity and composition with the fungal pH response and pathogenesis. IMPORTANCE The work described here further elucidates how microorganisms sense and adapt to changes in their environment to establish infections in the human host. Specifically, we uncover a novel mechanism by which an opportunistic human fungal pathogen, Cryptococcus neoformans, responds to increases in extracellular pH in order to survive and thrive within the relatively alkaline environment of the human lung. This mechanism, which is intimately linked with fungal membrane sterol homeostasis, is independent of the previously well-studied alkaline response Rim pathway. Furthermore, this ergosterol-dependent alkaline pH response is present in Candida albicans, indicating that this mechanism spans diverse fungal species. These results are also relevant for novel antimicrobial drug development as we show that currently used ergosterol-targeting antifungals are more active in alkaline environments.
format	article
author	Hannah E. Brown Calla L. Telzrow Joseph W. Saelens Larissa Fernandes J. Andrew Alspaugh
author_facet	Hannah E. Brown Calla L. Telzrow Joseph W. Saelens Larissa Fernandes J. Andrew Alspaugh
author_sort	Hannah E. Brown
title	Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi
title_short	Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi
title_full	Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi
title_fullStr	Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi
title_full_unstemmed	Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi
title_sort	sterol-response pathways mediate alkaline survival in diverse fungi
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/c647eac886b6428e9f7d9621b131927f
work_keys_str_mv	AT hannahebrown sterolresponsepathwaysmediatealkalinesurvivalindiversefungi AT callaltelzrow sterolresponsepathwaysmediatealkalinesurvivalindiversefungi AT josephwsaelens sterolresponsepathwaysmediatealkalinesurvivalindiversefungi AT larissafernandes sterolresponsepathwaysmediatealkalinesurvivalindiversefungi AT jandrewalspaugh sterolresponsepathwaysmediatealkalinesurvivalindiversefungi
_version_	1718427118985019392

Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi

Ejemplares similares